The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index; 30 of the 55 sources its claims cite were checked for support.
Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake
Open accessAbstract
Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Aster-B and Aster-C mediate non-vesicular cholesterol transport from the enterocyte plasma membrane to the ER downstream of NPC1L1, linking dietary cholesterol uptake to cholesteryl ester production. Loss or pharmacological inhibition of intestinal Asters impairs cholesterol absorption and protects mice from diet-induced hypercholesterolemia.
Key findings
- Combined loss of Aster-B and Aster-C reduced intestinal [14C]cholesterol absorption, with markedly lower absorption in the proximal intestine and reduced [14C]cholesterol in plasma and liver 2 h after gavage; single Aster-B or Aster-C knockouts showed no differences. Intestine-specific I-B/C-KO mice also had impaired fractional cholesterol absorption by fecal dual isotope labeling.
- Aster-deficient enterocytes accumulated accessible plasma membrane cholesterol and showed ER cholesterol depletion: ALOD4 staining was enhanced at the PM of Aster-B/C KO enteroids, jejunal cholesteryl ester was reduced after feeding, and SREBP-2 target gene/protein expression was elevated.
- After 21 days of a high-cholesterol diet, global B/C-KO and intestine-specific Aster-KO mice had reduced fasting plasma cholesterol and liver cholesterol, with lower cholesterol in VLDL/LDL and HDL fractions by FPLC.
- Ezetimibe bound Aster-B and Aster-C, and the crystal structure of the Aster-C ASTER domain with ezetimibe was solved at 1.6 Å resolution. The small-molecule Aster inhibitor AI-3d increased accessible PM cholesterol, induced SREBP-2 targets, and reduced dietary cholesterol absorption into the circulation in mice.
Methods
- Genetic mouse models included global Aster-B, Aster-C, and B/C knockouts; tamoxifen-inducible intestine-specific Aster-B, Aster-C, and B/C knockouts; 3×HA-Aster-B knock-in mice; and crosses to NPC1L1 KO mice.
- In vivo studies used gastric gavage with [14C]cholesterol, [14C]triolein, [13C]fatty acids plus [2H]cholesterol, d4-cholesterol, Poloxamer-407 injection, high-cholesterol diet, ezetimibe diet, and AI-3d treatment.
- Analyses included NanoSIMS imaging, lipidomics, RNA-seq, immunoblotting, immunohistochemistry, confocal microscopy of enteroids and cell lines, fecal dual isotope cholesterol absorption, FPLC, X-ray crystallography, and circular dichroism.
Limitations
- The paper states that the precise translational position of the PEG molecule in the Aster-C:ezetimibe crystal structure is uncertain because electron density weakened at one end.
- The discussion states that ezetimibe binding to Aster was not sufficient to block non-vesicular cholesterol transport in vivo, and that the data do not exclude the possibility that Asters retrieve cholesterol from NPC1L1-rich endosomes.
- Evident from the text: the main physiological and pharmacological findings are in mice, enteroids, and cell lines, with no human in vivo cholesterol-absorption or clinical outcome data; AI-3d safety assessment was limited to body weight and intestinal length.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
30 of 55 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Members of the Aster family have a central cholesterol-binding pocket flanked by a GRAM domain at the N-terminus and an ER transmembrane domain at the C-terminus.
“Members of this family have a central cholesterol-binding pocket that is flanked by a GRAM domain at the N-terminus and an ER transmembrane domain at the C-terminus.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [25] Sandhu J, Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell 175, 514– 529 (2018). 30220461 PMC6469685 source
- cites [26] Naito T, Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex. eLife 8, e51401 (2019). 31724953 PMC6905856 source
- cites [27] Besprozvannaya M, GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells. eLife 7, e31019 (2018). 29469807 PMC5823543 source
Figure 1A (Introduction) describes GRAMD1a–c as having a GRAM domain, a predicted sterol-transport VaST domain, and an ER-anchoring transmembrane domain. The Results describe the corresponding domain order, but the paper does not identify the VaST domain as a central cholesterol-binding pocket; that structural detail is not supported by this copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Free cholesterol deposited into the inner leaflet of the apical plasma membrane by NPC1L1 must subsequently move to the endoplasmic reticulum to be esterified by ACAT2.
“Free cholesterol deposited into the inner leaflet of the apical PM by NPC1L1 must subsequently move to the ER to be esterified by ACAT2 (3–5).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [3] Buhman KK, Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nature Medicine 6, 1341– 1347 (2000). 11100118 source
- cites [4] Nguyen TM, Sawyer JK, Kelley KL, Davis MA, Rudel LL, Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation [S]. Journal of Lipid Research 53, 95– 104 (2012). 22045928 PMC3243485 source
The Discussion (page unavailable) identifies ACAT2 as the major enzyme esterifying cholesterol in enterocytes and says lower NPC1L1 expression could limit cholesterol uptake. The paper does not establish that NPC1L1 deposits cholesterol in the inner leaflet of the apical membrane or that cholesterol must then move to the ER for esterification. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [5] Zhang J, Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood[S]. Journal of Lipid Research 53, 1144– 1152 (2012). 22460046 PMC3351821 source
The Abstract identifies ACAT2 as an enzyme that uses free cholesterol to synthesize cholesteryl esters in intestinal cells. The Discussion describes NPC1L1-mediated uptake from the intestinal lumen, but neither passage establishes that NPC1L1 deposits cholesterol in the inner leaflet of the apical membrane or that it must then move to the ER. Page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Rests on an assumption: Most cholesterol in chylomicrons is esterified, and cholesteryl ester is necessary for chylomicron packaging.
- Premisecitation
The recruitment of Asters to the PM depends on the cholesterol and phosphatidylserine content in the inner leaflet.
“The recruitment of Asters to the PM depends on the cholesterol and phosphatidylserine content in the inner leaflet (25, 26, 33).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [25] Sandhu J, Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell 175, 514– 529 (2018). 30220461 PMC6469685 source
The Results section reports cholesterol-dependent recruitment of Asters to the plasma membrane and shows that their GRAM domain binds phosphatidylserine. The Discussion identifies phosphatidylserine as enriched in the inner leaflet but says its binding *could* mediate recruitment; it does not establish that recruitment depends on inner-leaflet phosphatidylserine content or specifically measure inner-leaflet cholesterol content. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [26] Naito T, Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex. eLife 8, e51401 (2019). 31724953 PMC6905856 source
- cites [33] Ferrari A, Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane. Molecular and Cellular Biology 40, e00255– 00220 (2020). 32719109 PMC7491948 source
The Results report cholesterol-dependent recruitment of Asters to the plasma membrane in living cells and phosphatidylserine-dependent binding of the Aster-B GRAM domain to liposomes. The Discussion proposes that cholesterol alters phosphatidylserine presentation in the inner leaflet, but does not establish that recruitment in living cells depends on the inner leaflet’s phosphatidylserine content. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Findingown data
Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes.
“Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes.”
Quote in the paperSubstantial claim - Findingnone given
The Aster pathway can be targeted with a small molecule inhibitor to manipulate cholesterol uptake.
“Finally, the Aster pathway can be targeted with a small molecule inhibitor to manipulate cholesterol uptake.”
Quote in the paperSubstantial claim
- Findingown data
Confocal microscopy revealed enhanced ALOD4 staining at the plasma membrane of Aster-B/C KO enteroids loaded with MβCD-cholesterol.
“Confocal microscopy revealed enhanced ALOD4 staining at the PM of Aster-B/C KO enteroids loaded with MβCD-cholesterol (Fig. 2C), consistent with reduced cholesterol movement to ER.”
Quote in the paperSubstantial claim - Findingown data
No changes in SREBP-2 pathway expression were observed in the jejunum of global or intestinal-specific single-KO mice.
“We did not observe changes in SREBP-2 pathway expression in the jejunum of global (Fig. S6, D and E) or intestinal-specific (Fig. S6, F and G) single-KO mice.”
Quote in the paperNot a substantial claim - Findingown data
Absolute quantification of Gramd1 transcripts in intestinal epithelial cells confirmed those for Aster-B and -C were most abundant.
“Absolute quantification of Gramd1 transcripts in intestinal epithelial cells confirmed those for Aster-B and -C were most abundant (Fig. S1B).”
Quote in the paperNot a substantial claim - Findingown data
Cholesterol uptake was similar in I-B KO, I-C-KO, and littermate control mice.
“Cholesterol uptake was similar in I-B KO, I-C-KO, and littermate control mice (Fig. S3I–N).”
Quote in the paperSubstantial claim - Findingown data
There were no detectable reductions in 14C counts in intestinal segments, plasma, and liver of I-B/C-KO mice after an oral gavage of [14C]triolein.
“By contrast, there were no detectable reductions in 14C counts in intestinal segments, plasma, and liver of I-B/C-KO mice after an oral gavage of [14C]triolein (Fig. S4A–D).”
Quote in the paperSubstantial claim - Findingown data
Plasma levels of ApoB48 after refeeding with a high-cholesterol diet were not different between groups.
“Plasma levels of ApoB48 after refeeding with a HC diet were not different between groups (Fig. 3G and H), despite lower plasma cholesterol levels in I-B/C KO mice (Fig. 3I).”
Quote in the paperSubstantial claim - Findingown data
Ezetimibe decreased cholesteryl ester content and fractional cholesterol absorption by the fecal dual isotope method in wild-type mice.
“As expected, EZ decreased CE content and fractional cholesterol absorption by the fecal dual isotope method in WT mice (Fig. 6A–C).”
Quote in the paperSubstantial claim - Findingown data
Upregulation of Srebf2 and its targets was observed in jejunal scrapings in B/C-KO mice fed a high-cholesterol diet.
“We also observed upregulation of Srebf2 and its targets in jejunal scrapings in B/C-KO mice fed a high-cholesterol (HC) diet (1.25% cholesterol) (Fig. S6C).”
Quote in the paperSubstantial claim - Findingown data
After 21 days of a high-cholesterol diet, global B/C-KO mice had a modest decrease in weight.
“After 21 days of a HC diet, we observed a modest decrease in the weight of global B/C-KO mice (Fig. 4A), accompanied by reduced fasting plasma cholesterol levels (Fig. 4B).”
Quote in the paperNot a substantial claim - Findingown data
SREBP-2 pathway gene and protein expression was elevated in global B/C-KO and I-B/C-KO mice compared to controls.
“SREBP-2 pathway gene and protein expression (Fig. 4G–I) was elevated in global B/C-KO and I-B/C-KO mice compared to controls.”
Quote in the paperSubstantial claim - Findingown data
Lipidomic analysis of jejunal scrapings revealed reduced cholesteryl ester in B/C-KO mice after feeding.
“Accordingly, lipidomic analysis of jejunal scrapings revealed reduced CE in B/C-KO mice after feeding (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
Fractional cholesterol absorption, assessed by fecal dual isotope labeling, confirmed impaired cholesterol absorption in I-B/C-KO mice.
“Fractional cholesterol absorption, assessed by fecal dual isotope labeling, confirmed impaired cholesterol absorption in I-B/C-KO mice (Fig. 1J).”
Quote in the paperSubstantial claim - Findingown data
Plasma triglyceride levels were similar between groups.
“Plasma triglyceride levels were similar between groups (Fig. S7A and B).”
Quote in the paperNot a substantial claim - Findingown data
The overall structure of the Aster-C domain revealed a canonical curved seven-stranded beta-sheet that forms a cavity to accommodate ezetimibe.
“The overall structure of the Aster-C domain revealed a canonical curved seven-stranded beta-sheet that forms a cavity to accommodate EZ (Fig. 5B, Table S3).”
Quote in the paperSubstantial claim - Findingown data
Gene-expression and protein analyses revealed stronger activation of the SREBP-2 pathway in Aster-B/C-KO mice on the ezetimibe diet compared to either Aster-B/C KO mice or ezetimibe-treated WT mice.
“However, gene-expression and protein analyses revealed stronger activation of the SREBP-2 pathway in Aster-B/C-KO mice on the EZ diet compared to either Aster-B/C KO mice or EZ-treated WT mice (Fig. S9B and Fig. 6D).”
Quote in the paperSubstantial claim - Findingown data
Transcripts for Aster-A, -B, and -C are expressed in the small intestine.
“Transcripts for Aster-A, -B, and -C are expressed in the small intestine (SI) (Fig. 1A), and RNA-seq from proximal jejunal scrapings of C57BL6/J mice confirmed robust expression of Gramd1b and Gramd1c and low expression of Gramd1a (Fig. S1A).”
Quote in the paperSubstantial claim - Findingown data
RNA-seq from proximal jejunal scrapings of C57BL6/J mice confirmed robust expression of Gramd1b and Gramd1c and low expression of Gramd1a.
“RNA-seq from proximal jejunal scrapings of C57BL6/J mice confirmed robust expression of Gramd1b and Gramd1c and low expression of Gramd1a (Fig. S1A).”
Quote in the paperNot a substantial claim - Findingown data
Aster-B was expressed along the entire length of the small intestine (duodenum to the ileum).
“Aster-B was expressed along the entire length of the SI (duodenum to the ileum) (Fig. S1C).”
Quote in the paperNot a substantial claim - Findingown data
There was a greater distribution of HA-Aster-B at the brush border of enterocytes 1 h after intra-gastric gavage with cholesterol in corn oil versus corn oil alone.
“Accordingly, immunohistochemistry showed a greater distribution of HA-Aster-B at the brush border of enterocytes 1 h after intra-gastric gavage with cholesterol in corn oil versus corn oil alone (Fig. 1DC”
Quote in the paperSubstantial claim - Findingown data
An intestine-specific promoter in the Gramd1b locus defined the longer variant.
“An intestine-specific promoter in the Gramd1b locus (chr9: 40465470–40465756) defined the longer variant.”
Quote in the paperNot a substantial claim - Findingown data
Many residues involved in ligand interactions are conserved in Aster-A and Aster-C.
“Many of the residues involved in ligand interactions are conserved in Aster-A and Aster-C (Fig. S8F).”
Quote in the paperNot a substantial claim - Findingown data
NanoSIMS images revealed reduced amounts of 2H in medial and distal segments of the duodenum in B/C-KO mice.
“NanoSIMS images of the same sections (Fig. 2A, Fig. S5A) revealed reduced amounts of 2H in medial and distal segments of the duodenum in B/C-KO mice.”
Quote in the paperSubstantial claim - Findingown data
Ezetimibe completely prevented the recruitment of Aster-B to the brush border after cholesterol gavage.
“Remarkably, EZ completely prevented the recruitment of Aster-B to the brush border after cholesterol gavage (Fig. 6E).”
Quote in the paperSubstantial claim - Findingown data
Global B/C-KO mice had reduced fasting plasma cholesterol levels.
“After 21 days of a HC diet, we observed a modest decrease in the weight of global B/C-KO mice (Fig. 4A), accompanied by reduced fasting plasma cholesterol levels (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
SREBP-2 target gene expression was higher in global B/C-KO than in WT mice, both in fasted and refed states.
“SREBP-2 target gene expression was higher in global B/C-KO than in WT mice, both in fasted and refed states (Fig. 3C, D), consistent with reduced ER cholesterol.”
Quote in the paperSubstantial claim - Findingown data
In Caco-2 cells, transcripts for Aster-B and -C were induced upon differentiation.
“In Caco-2 cells, transcripts for Aster-B and -C were induced upon differentiation (Fig. S1D).”
Quote in the paperNot a substantial claim - Findingown data
Quantification of 13C− and 2H− secondary ions confirmed reduced cholesterol uptake by enterocytes lacking Asters.
“Quantification of 13C− and 2H− secondary ions confirmed reduced cholesterol uptake by enterocytes lacking Asters (Fig. 2B, Fig. S5B).”
Quote in the paperSubstantial claim - Findingown data
NPC1L1 and Asters play sequential, non-redundant roles in the delivery of dietary cholesterol from the intestinal lumen to the enterocyte ER.
“Here we show NPC1L1 and Asters and play sequential, non-redundant roles in the delivery of dietary cholesterol from the intestinal lumen to the enterocyte ER.”
Quote in the paperSubstantial claim - Findingown data
B/C-KO mice had reduced amounts of [14C]cholesterol in the plasma and liver 2 h after gavage.
“B/C-KO mice also had reduced amounts of [14C]cholesterol in the plasma and liver 2 h after gavage (Fig. 1, E and F).”
Quote in the paperSubstantial claim - Findingown data
B/C-KO mice had markedly reduced [14C]cholesterol absorption in the proximal intestine.
“No differences in [14C]cholesterol absorption were detected in single-KO mice (Fig. S2 H–M), but we observed markedly reduced absorption in the proximal intestine of B/C-KO mice (Fig. 1D, Fig. S2N and O).”
Quote in the paperSubstantial claim - Findingown data
The most abundant Gramd1c transcript in the small intestine encodes a truncated Aster-C lacking the N-terminal GRAM domain.
“The most abundant Gramd1c transcript in the SI encodes a truncated Aster-C lacking the N-terminal GRAM domain.”
Quote in the paperNot a substantial claim - Findingown data
I-B/C KO mice had reduced d4-cholesteryl ester in chylomicrons without changes in d4-cholesterol compared to floxed control mice.
“I-B/C KO mice had reduced d4-CE in chylomicrons (Fig. 3K) without changes in d4-cholesterol compared to floxed control mice (Fig. 3L).”
Quote in the paperSubstantial claim - Findingown data
HA-Aster-B was enriched in the villi of the jejunum with lower expression in the crypts.
“Immunohistochemistry of intestinal tissue revealed that HA-Aster-B was enriched in the villi of the jejunum with lower expression in the crypts (Fig. S1H).”
Quote in the paperNot a substantial claim - Findingown data
No differences in [14C]cholesterol absorption were detected in single-KO mice.
“No differences in [14C]cholesterol absorption were detected in single-KO mice (Fig. S2 H–M), but we observed markedly reduced absorption in the proximal intestine of B/C-KO mice (Fig. 1D, Fig. S2N and O).”
Quote in the paperSubstantial claim - Findingown data
When enteroids were loaded with MβCD cholesterol, ALOD4 binding was not different between NPC1L1KO and WT enteroids.
“When enteroids were loaded with MβCD cholesterol, ALOD4 binding was not different between NPC1L1KO and WT enteroids (Fig. 6F, bottom panels).”
Quote in the paperSubstantial claim - Findingown data
Liver cholesterol levels were reduced in global B/C-KO mice.
“Liver cholesterol levels were also reduced (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
The crystal structure at 1.6 Å resolution of the ASTER domain from Aster-C complexed to ezetimibe was solved.
“Next, we solved the crystal structure, at 1.6 Å resolution, of the ASTER domain from Aster-C complexed to EZ.”
Quote in the paperSubstantial claim - Findingown data
FPLC fractionation of plasma revealed lower cholesterol levels in the VLDL/LDL and HDL fractions from Aster-KO mice.
“FPLC fractionation of plasma revealed lower cholesterol levels in the VLDL/LDL and HDL fractions from Aster-KO mice (Fig. 4F).”
Quote in the paperSubstantial claim - Findingown data
Glucose absorption was not impacted in I-B/C-KO mice.
“Glucose absorption was not impacted in I-B/C-KO mice (Fig. S4E).”
Quote in the paperSubstantial claim - Findingown data
Protein levels of SREBP-2 targets in duodenal scrapings were elevated in B/C-KO mice.
“Protein levels of SREBP-2 targets in duodenal scrapings were correspondingly elevated in B/C-KO mice (Fig. 3F).”
Quote in the paperSubstantial claim - Findingown data
The level of free [14C]cholesterol was similar between groups.
“The level of free [14C]cholesterol was similar between groups (Fig. S6B).”
Quote in the paperSubstantial claim - Findingown data
Aster-B was recruited to the plasma membrane in response to loading with methyl-β-cyclodextrin-cholesterol in enteroids.
“Confocal imaging demonstrated that Aster-B was recruited to the PM in response to loading with methyl-β-cyclodextrin (MβCD)–cholesterol (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
There were fewer 14C counts in the chylomicron fraction of plasma isolated 2 h after oral gavage of [14C]cholesterol in I-B/C KO mice versus control mice.
“In support of this conclusion, there were fewer 14C counts in the chylomicron fraction of plasma isolated 2 h after oral gavage of [14C]cholesterol in I-B/C KO mice versus control mice (Fig. 3J).”
Quote in the paperSubstantial claim - Findingown data
Other lipid species were not affected by Aster deficiency.
“Other lipid species were not affected by Aster deficiency (Fig. S6A).”
Quote in the paperSubstantial claim - Findingown data
14C-labeled cholesteryl ester accumulation was reduced in the proximal jejunum of Aster-deficient mice 2 h after oral administration of [14C]cholesterol in olive oil.
“Consistent with these findings, 14C-labeled CE accumulation was reduced in the proximal jejunum of Aster-deficient mice 2 h after oral administration of [14C]cholesterol in olive oil (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Plasma triglyceride levels were comparable.
“Plasma triglyceride levels were also comparable (Fig. S6H), consistent with our observation that fatty acid absorption was unaffected by loss of Asters (Fig. S4A–D).”
Quote in the paperSubstantial claim - Findingown data
Similar findings were observed in jejunal scrapings of I-B/C-KO mice.
“Similar findings were observed in jejunal scrapings of I-B/C-KO mice (Fig. 3E).”
Quote in the paperNot a substantial claim - Findingown data
Treatment of wild-type mice with the LXR agonist GW3965 induced the expression of all three Asters in the small intestine.
“Treatment of WT mice with the LXR agonist GW3965 induced the expression of all three Asters in the SI (Fig. S1E), consistent with a role for the Aster pathway in intestinal cholesterol flux.”
Quote in the paperSubstantial claim - Findingown data
I-B/C-KO mice had reduced [14C]cholesterol absorption compared to floxed controls.
“However, I-B/C-KO mice had reduced [14C]cholesterol absorption compared to floxed controls (similar to global B/C-KO mice) (Fig. 1G–I).”
Quote in the paperSubstantial claim - Findingown data
Aster deficiency did not provide an additional decrease in cholesteryl ester or cholesterol absorption in ezetimibe-treated mice.
“Aster deficiency did not provide an additional decrease in CE or cholesterol absorption in EZ-treated mice (Fig. 6A–C).”
Quote in the paperSubstantial claim - Findingown data
Pharmacologic inhibition of Asters reduced dietary cholesterol absorption into the circulation in C57BL/6J mice.
“EZ treatment and pharmacologic inhibition of Asters both reduced dietary cholesterol absorption into the circulation (Fig. 7D).”
Quote in the paperSubstantial claim - Findingown data
Aster proteins do not translocate to the enterocyte PM when NPC1L1 is deleted or inhibited by EZ.
“Aster proteins do not translocate to the enterocyte PM when NPC1L1 is deleted or inhibited by EZ.”
Quote in the paperSubstantial claim - Findingown data
AI-3d generates a similar effect in human jejunal enteroids.
“AI-3d generated a similar effect in human jejunal enteroids (Fig. 7B)”
Quote in the paperSubstantial claim - Findingown data
NPC1L1-EGFP was present within a recycling compartment when both vehicle-treated and AI-3d treated cells were cultured in full serum.
“we observed that NPC1L1-EGFP was present within a recycling compartment when both vehicle-treated and AI-3d treated cells were cultured in full serum (Fig. S10I, left panels).”
Quote in the paperSubstantial claim - Findingown data
In response to cholesterol depletion by MβCD, the signal in both cell types moved to the PM.
“In response to cholesterol depletion by MβCD, the signal in both cell types moved to the PM (Fig. S10I, middle panels).”
Quote in the paperSubstantial claim - Findingown data
Aster deletion further reduced ER cholesterol delivery in the presence of EZ.
“as Aster deletion further reduced ER cholesterol delivery in the presence of EZ.”
Quote in the paperSubstantial claim - Findingown data
In WT enteroids treated with AI-3d and MβCD cholesterol, accessible cholesterol accumulates.
“Treatment of WT enteroids with AI-3d and MβCD cholesterol led to an accumulation of accessible cholesterol”
Quote in the paperSubstantial claim - Findingown data
Lipidomic analysis revealed reduced CE in jejunal scrapings from NPC1L1 KO compared to WT mice.
“Lipidomic analysis revealed reduced CE in jejunal scrapings from NPC1L1 KO compared to WT mice.”
Quote in the paperNot a substantial claim - Findingreasoning
Micelle-derived cholesterol cannot contribute to the expansion of the accessible pool.
“micelle-derived cholesterol cannot contribute to the expansion of the accessible pool”
Quote in the paperSubstantial claim - Findingown data
EZ binding to Aster was not sufficient to block non-vesicular cholesterol transport in vivo in our studies.
“However, EZ binding to Aster was not sufficient to block non-vesicular cholesterol transport in vivo in our studies”
Quote in the paperSubstantial claim - Findingreasoning
When NPC1L1 is bypassed by delivering cholesterol directly to the PM with MβCD, Aster is recruited normally.
“However, when NPC1L1 is bypassed by delivering cholesterol directly to the PM with MβCD, Aster is recruited normally.”
Quote in the paperSubstantial claim - Findingnone given
Aster-B/C knockout mice have low plasma cholesterol levels when fed a western diet enriched in cholesterol.
“First, Aster-B/C knockout mice have low plasma cholesterol levels when fed a western diet enriched in cholesterol.”
Quote in the paperSubstantial claim - Findingreasoning
Aster deletion does not further decrease absorption when NPC1L1 is blocked.
“In this context, Aster deletion does not further decrease absorption, because the apical PM cholesterol available for transfer is limited.”
Quote in the paperSubstantial claim - Findingnone given
EZ binds to Aster-B and -C with moderate affinity.
“EZ binds to Aster-B and -C with moderate affinity”
Quote in the paperSubstantial claim - Findingown data
EZ treatment reduced dietary cholesterol absorption into the circulation in C57BL/6J mice.
“EZ treatment and pharmacologic inhibition of Asters both reduced dietary cholesterol absorption into the circulation (Fig. 7D).”
Quote in the paperSubstantial claim - Findingown data
Genetic ablation of NPC1L1 abolished Aster-B movement to the brush border in response to cholesterol loading, mirroring the effects of ezetimibe.
“Analysis of HA-B-NPC1L1 WT and HA-B-NPC1L1 KO mice confirmed that genetic ablation of NPC1L1 abolished Aster-B movement to the brush border in response to cholesterol loading, mirroring the effects of EZ (Fig. 6G and S9E).”
Quote in the paperSubstantial claim - Findingown data
AI-3d increased SREBP-2 target gene expression in human enteroids and differentiated Caco-2 cells.
“AI-3d increased SREBP-2 target gene expression in human enteroids (Fig. 7C) and differentiated Caco-2 cells (Fig. S10D).”
Quote in the paperSubstantial claim - Findingown data
MβCD-cholesterol loading led to the relocation of NPC1L1-EGFP to endosomes.
“Conversely, MβCD-cholesterol loading led to the relocation of NPC1L1-EGFP to endosomes (Fig. S10I, right panels).”
Quote in the paperNot a substantial claim - Findingown data
Aster inhibition by AI-3d lowered levels of jejunal CE similarly in WT and NPC1L1 KO.
“Aster inhibition by AI-3d lowered levels of jejunal CE similarly in WT and NPC1L1 KO”
Quote in the paperSubstantial claim - Findingown data
Treatment of mice with AI-3d inhibited cholesterol absorption.
“Finally, treatment of mice with AI-3d inhibited cholesterol absorption.”
Quote in the paperSubstantial claim - Findingown data
CE production in the ER is markedly impaired by Aster deletion even when NPC1L1 is present.
“the observation that CE production in the ER is markedly impaired by Aster deletion even when NPC1L1 is present”
Quote in the paperSubstantial claim - Findingown data
When enteroids were loaded with MβCD-cholesterol, AI-3d treatment increased ALOD4 binding similarly in WT and NPC1L1 KO cells.
“However, when enteroids were loaded with MβCD-cholesterol, AI-3d treatment increased ALOD4 binding similarly in WT and NPC1L1 KO cells (Fig. S10C).”
Quote in the paperSubstantial claim - Findingown data
In B/C-KO enteroids, AI-3d has no additional effect on ALOD4 binding.
“AI-3d had no additional effect on ALOD4 binding in B/C-KO enteroids (Fig. 7A, fig. S10A).”
Quote in the paperSubstantial claim - Findingown data
When enteroids were loaded with MM cholesterol, AI-3d treatment increased ALOD4 binding only in NPC1L1 WT cells.
“When enteroids were loaded with MM cholesterol, AI-3d treatment increased ALOD4 binding only in NPC1L1 WT cells (Fig. S10B).”
Quote in the paperSubstantial claim - Findingown data
Gene expression analysis showed a further induction of SREBP2 targets in NPC1L-KO mice treated with AI-3d.
“Gene expression analysis showed a further induction of SREBP2 targets in NPC1L-KO mice treated with AI-3d (Fig. 7F).”
Quote in the paperNot a substantial claim - Study design and conductown data
Deletion of Asters was verified in jejunal scrapings.
“Deletion of Asters was verified in jejunal scrapings (Fig. S2C, D, and E).”
Quote in the paperSubstantial claim - Study design and conductown data
The small intestine from B/C-KO mice had no obvious histological abnormalities.
“The SI from B/C-KO mice had no obvious histological abnormalities (Fig. S2F), and body weight and intestinal length showed minimal differences across genotypes (Fig. S2G).”
Quote in the paperNot a substantial claim - Interpretationown data
Delivery of cholesterol in MβCD effectively bypasses the function of NPC1L1.
“Thus, delivery of cholesterol in MβCD effectively bypasses the function of NPC1L1.”
Quote in the paperSubstantial claim - Interpretationown data
Induction of Asters by LXR agonist is consistent with a role for the Aster pathway in intestinal cholesterol flux.
“Treatment of WT mice with the LXR agonist GW3965 induced the expression of all three Asters in the SI (Fig. S1E), consistent with a role for the Aster pathway in intestinal cholesterol flux.”
Quote in the paperNot a substantial claim - Premisecitation
Ezetimibe blocks the channel within NPC1L1 required for cholesterol deposition into the plasma membrane.
“EZ blocks the channel within NPC1L1 required for cholesterol deposition into the PM (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Huang C-S, Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition. Science Advances 6, eabb1989 (2020). 32596471 PMC7304964 source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
Loss of Aster expression does not appear to compromise intestinal development.
“Thus, loss of Aster expression does not appear to compromise intestinal development.”
Quote in the paperNot a substantial claim - Interpretationown data
Higher SREBP-2 target gene expression is consistent with reduced ER cholesterol.
“SREBP-2 target gene expression was higher in global B/C-KO than in WT mice, both in fasted and refed states (Fig. 3C, D), consistent with reduced ER cholesterol.”
Quote in the paperSubstantial claim - Study design and conductown data
I-B/C KO mice displayed normal crypt cell proliferation as revealed by OLFM4 staining.
“I-B/C KO mice displayed normal crypt cell proliferation as revealed by OLFM4 staining (Fig. S3G).”
Quote in the paperSubstantial claim - Interpretationown data
Loss of Aster function in enterocytes selectively impairs cholesterol absorption.
“Thus, loss of Aster function in enterocytes selectively impairs cholesterol absorption.”
Quote in the paperSubstantial claim - Interpretationreasoning
The principal function of NPC1L1 is to enrich the enterocyte plasma membrane with dietary cholesterol.
“Our findings support a model in which the principal function of NPC1L1 is to enrich the enterocyte PM with dietary cholesterol.”
Quote in the paperSubstantial claim - Interpretationown data
Enhanced ALOD4 staining is consistent with reduced cholesterol movement to the ER.
“Confocal microscopy revealed enhanced ALOD4 staining at the PM of Aster-B/C KO enteroids loaded with MβCD-cholesterol (Fig. 2C), consistent with reduced cholesterol movement to ER.”
Quote in the paperSubstantial claim - Interpretationown data
Even in the setting of increased dietary cholesterol, cholesterol synthesis was activated in B/C-KO mice.
“Thus, even in the setting of increased dietary cholesterol, cholesterol synthesis was activated in B/C-KO mice.”
Quote in the paperSubstantial claim - Interpretationown data
De novo cholesterol synthesis was activated in KO intestine even in the setting of excess dietary cholesterol.
“Thus, de novo cholesterol synthesis was activated in KO intestine even in the setting of excess dietary cholesterol (Fig. 4H, 4I).”
Quote in the paperSubstantial claim - Interpretationreasoning
NPC1L1 and Asters function in series to move cholesterol from the diet into the circulation.
“Thus, NPC1L1 and Asters function in series to move cholesterol from the diet into the circulation.”
Quote in the paperSubstantial claim- The authors state this as an assumption: How cholesterol that enters the cell via NPC1L1 reaches the ER for esterification and regulation of cholesterol synthesis was a long-standing mystery.
- Interpretationreasoning
The sterol-regulated endocytosis of NPC1L1 could represent a feedback mechanism to limit cholesterol absorption, rather than a major mechanism for vesicular cholesterol transfer to the ER.
“We propose that the sterol-regulated endocytosis of NPC1L1 could represent a feedback mechanism to limit cholesterol absorption, rather than a major mechanism for vesicular cholesterol transfer to the ER.”
Quote in the paperSubstantial claim - Interpretationown data
NPC1L1 deposits micellular cholesterol into the PM to expand the accessible pool.
“Thus, NPC1L1 deposits micellular cholesterol into the PM to expand the accessible pool”
Quote in the paperSubstantial claim - Interpretationown data
Aster-B and -C link NPC1L1 to ACAT2 by facilitating non-vesicular cholesterol transport to the ER following uptake by NPC1L1 at the enterocyte PM.
“Here we solve that mystery by showing that Aster-B and -C link NPC1L1 to ACAT2 by facilitating non-vesicular cholesterol transport to the ER following uptake by NPC1L1 at the enterocyte PM.”
Quote in the paperSubstantial claim- The authors state this as an assumption: How cholesterol that enters the cell via NPC1L1 reaches the ER for esterification and regulation of cholesterol synthesis was a long-standing mystery.
- The authors state this as an assumption: Formal tests of the relative contribution of vesicular and non-vesicular cholesterol transport mechanisms downstream of NPC1L1 have been lacking.
- Interpretationown data
Combined deletion of Aster-B and -C impairs the movement of dietary cholesterol to ER in enterocytes.
“Combined deletion of Aster-B and -C impairs the movement of dietary cholesterol to ER in enterocytes”
Quote in the paperSubstantial claim - Premisecitation
AI-3d potently inhibits Aster-A, -B, and -C.
“Previous work from our laboratory identified a small molecule, AI-3d, that potently inhibits Aster-A, -B, and -C (36).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Xiao X, Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms. Proceedings of the National Academy of Sciences 118, e2024149118 (2021). PMC7812747 33376205 source
- Interpretationown data
Aster-mediated non-vesicular transport relies on NPC1L1 to deposit cholesterol into the apical enterocyte PM, rather than on a direct physical interaction with NPC1L1.
“Our results support the notion that Aster-mediated non-vesicular transport relies on NPC1L1 to deposit cholesterol into the apical enterocyte PM, rather than on a direct physical interaction with NPC1L1.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Formal tests of the relative contribution of vesicular and non-vesicular cholesterol transport mechanisms downstream of NPC1L1 have been lacking.
- Interpretationown data
AI-3d treatment does not interfere with the process of NPC1L1 recycling.
“These results indicate that AI-3d treatment does not interfere with the process of NPC1L1 recycling”
Quote in the paperSubstantial claim - Interpretationown data
MβCD bypasses the NPC1L1 function of depositing micellular cholesterol into the PM.
“and MβCD bypasses this function.”
Quote in the paperSubstantial claim - Interpretationown data
AI-3d supports the absence of toxicity.
“supporting the absence of toxicity.”
Quote in the paperNot a substantial claim - Interpretationown data
The primary function of NPC1L1 is to deposit dietary cholesterol into the enterocyte PM.
“Our data indicate that the primary function of NPC1L1 is to deposit dietary cholesterol into the enterocyte PM.”
Quote in the paperSubstantial claim - Interpretationown data
Ezetimibe prevents Aster translocation to the brush border via NPC1L1 blockade.
“These results substantiate the hypothesis that EZ prevents Aster translocation to the brush border via NPC1L1 blockade.”
Quote in the paperSubstantial claim - Interpretationown data
The contrasting behavior of NPC1L1 and Aster in response to cholesterol loading argues against a direct physical interaction between the two proteins during cholesterol import.
“This contrasting behavior of NPC1L1 and Aster in response to cholesterol loading argues against a direct physical interaction between the two proteins during cholesterol import.”
Quote in the paperSubstantial claim - Interpretationown data
The Aster pathway can be targeted pharmacologically to reduce cholesterol absorption.
“Second, we showed that the Aster pathway can be targeted pharmacologically to reduce cholesterol absorption.”
Quote in the paperSubstantial claim - Interpretationown data
AI-3d does not act through NPC1L1.
“indicating that AI-3d does not act through NPC1L1 (Fig. 7E).”
Quote in the paperSubstantial claim - Premisereasoning
Cholesterol absorption is reduced when NPC1L1 is blocked by EZ.
“cholesterol absorption is reduced when NPC1L1 is blocked by EZ.”
Quote in the paperSubstantial claim - Interpretationreasoning
AI-3d inhibits cholesterol absorption by targeting Asters.
“further supporting the conclusion that AI-3d inhibits cholesterol absorption by targeting Asters.”
Quote in the paperSubstantial claim - Interpretationown data
This argues against a dominant role for NPC1L1 itself in cholesterol transport to the ER.
“argues against a dominant role for NPC1L1 itself in cholesterol transport to the ER.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 50
- Probably not a substantial claim. 23
It may state two separate claims as one.
Findingown dataRNA-seq revealed two transcripts for Gramd1b in the intestine; one was the same as that identified previously in macrophages, while the other had an extended N-terminal region upstream of the GRAM domain.
“RNA-seq also revealed the presence of two transcripts for Gramd1b in the intestine; one was the same as that identified previously in macrophages (25), while the other had an extended N-terminal region upstream of the GRAM domain (Fig. S1A).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Sandhu J, Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell 175, 514– 529 (2018). 30220461 PMC6469685 source
It may state two separate claims as one.
PremisecitationThe combination of ezetimibe and a statin further reduces cardiovascular events compared to statin alone, validating the intestine as a therapeutic target for the regulation of cholesterol homeostasis.
“The combination of EZ and a statin further reduces cardiovascular events compared to statin alone (10), validating the intestine as a therapeutic target for the regulation of cholesterol homeostasis.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [10] Cannon CP, Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. New England Journal of Medicine 372, 2387– 2397 (2015). 26039521 source
Probably not a substantial claim.
PremisecitationPrevious studies showed that in macrophages and hepatocytes Asters specifically recognize the accessible pool of plasma membrane cholesterol.
“Previous studies showed that in macrophages (33) and hepatocytes (28) Asters specifically recognize the accessible pool of PM cholesterol (34, 35).”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [33] Ferrari A, Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane. Molecular and Cellular Biology 40, e00255– 00220 (2020). 32719109 PMC7491948 source
The Results and Discussion report that Aster deficiency expands the accessible plasma-membrane cholesterol pool in mouse macrophages, and the Results show that an Aster GRAM domain recognizes cholesterol in the presence of phosphatidylserine. The paper examines macrophages and fibroblasts, not hepatocytes, and does not establish that Asters specifically recognize the accessible pool in hepatocytes. The indexed passages provide no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [28] Xiao X, Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis. Nature Metabolism 5, 165– 181 (2023). PMC9995220 36646756 source
The Abstract Body (page not given) says accessible plasma-membrane cholesterol engages the Aster pathway in the liver, supporting the hepatocyte connection. It does not establish that Asters specifically recognize that cholesterol pool. The macrophage finding is separately attributed to citation 33 in the citing sentence. (LLM, conf=0.80)
Experimental — accuracy not yet measured - cites [34] Das A, Brown MS, Anderson DD, Goldstein JL, Radhakrishnan A, Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. LID - 10.7554/eLife.02882 [doi] LID - e02882. (2014). PMC4086274 24920391 source
The Abstract describes a plasma-membrane cholesterol pool accessible to PFO* in human fibroblasts, not recognition of that pool by Asters. A search of the full-text copy for Asters and for the claimed macrophage and hepatocyte contexts found no passage addressing Aster recognition. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [35] Gay A, Rye D, Radhakrishnan A, Switch-like Responses of Two Cholesterol Sensors Do Not Require Protein Oligomerization in Membranes. Biophysical Journal 108, 1459– 1469 (2015). 25809258 PMC4375629 source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationCholesterol is absorbed by enterocytes and packaged into chylomicrons, which are released into the lymphatics and ultimately reach the systemic circulation.
“Cholesterol is absorbed by enterocytes and packaged into chylomicrons, which are released into the lymphatics and ultimately reach the systemic circulation (2).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] Mansbach CM, Siddiqi SA, The Biogenesis of Chylomicrons. Annual Review of Physiology 72, 315– 333 (2010). PMC4861230 20148678 source
It may state two separate claims as one.
PremisecitationThe GRAM domain binds the plasma membrane in response to cholesterol loading, allowing Asters to transfer cholesterol down a concentration gradient from the plasma membrane to the ER.
“The GRAM domain binds the PM in response to cholesterol loading, allowing Asters to transfer cholesterol down a concentration gradient from the PM to the ER.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [25] Sandhu J, Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell 175, 514– 529 (2018). 30220461 PMC6469685 source
- cites [26] Naito T, Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex. eLife 8, e51401 (2019). 31724953 PMC6905856 source
The Results section on GRAM-domain sensing reports that cholesterol loading recruits GRAMD1s to the plasma membrane and that removing the GRAM domain prevents this recruitment. The Discussion (Figure 8) says GRAMD1s transport accessible cholesterol from the PM to the ER. Our copy does not establish that this transfer occurs down a concentration gradient; it also specifies that GRAM-domain binding responds to accessible cholesterol together with anionic lipids. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [27] Besprozvannaya M, GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells. eLife 7, e31019 (2018). 29469807 PMC5823543 source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
PremisecitationAster proteins bind cholesterol and facilitate its movement between membranes.
“Aster proteins (Aster-A, -B, and -C; encoded by Gramd1a, Gramd1b, and Gramd1c) bind cholesterol and facilitate its movement between membranes (25–27).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [25] Sandhu J, Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell 175, 514– 529 (2018). 30220461 PMC6469685 source
- cites [26] Naito T, Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex. eLife 8, e51401 (2019). 31724953 PMC6905856 source
- cites [27] Besprozvannaya M, GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells. eLife 7, e31019 (2018). 29469807 PMC5823543 source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationNPC1L1 is a target of the drug ezetimibe.
“NPC1L1 is a target of the drug ezetimibe (EZ) (8–10).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [8] Garcia-Calvo M, The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proceedings of the National Academy of Sciences 102, 8132– 8137 (2005). PMC1149415 15928087 source
- cites [9] Davis HR, Pula KK, Alton KB, Burrier RE, Watkins RW, The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs. Metabolism 50, 1234– 1241 (2001). 11586500 source
- cites [10] Cannon CP, Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. New England Journal of Medicine 372, 2387– 2397 (2015). 26039521 source
Probably not a substantial claim.
PremisecitationNPC1L1 is an important mediator of intestinal cholesterol uptake.
“Niemann-Pick C1-Like 1 (NPC1L1) is an important mediator of intestinal cholesterol uptake (6, 7), but how cholesterol is delivered to the enterocyte ER for esterification remains to be defined.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [6] Altmann Scott W, Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303, 1201– 1204 (2004). 14976318
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7] Davis HR Jr., Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis. Journal of Biological Chemistry 279, 33586– 33592 (2004). 15173162 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLiver X receptor transcription factors are key regulators of cholesterol metabolism.
“Liver X receptor transcription factors are key regulators of cholesterol metabolism (29, 30).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [29] Wang B, Tontonoz P, Liver X receptors in lipid signalling and membrane homeostasis. Nature Reviews Endocrinology 14, 452– 463 (2018). PMC6433546 29904174 source
- cites [30] Yu L, Expression of ABCG5 and ABCG8 Is Required for Regulation of Biliary Cholesterol Secretion. Journal of Biological Chemistry 280, 8742– 8747 (2005). 15611112 source
It may state two separate claims as one.
PremisecitationIn mice, Aster-B is required for cholesteryl ester storage and corticosteroid synthesis in the adrenal cortex.
“In mice, Aster-B is required for CE storage and corticosteroid synthesis in the adrenal cortex (25), while Aster-C is important for hepatic reverse cholesterol transport (28).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Sandhu J, Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell 175, 514– 529 (2018). 30220461 PMC6469685 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationStructural analyses have revealed that the N-terminal domain of NPC1L1 possesses a cavity that accommodates cholesterol.
“Structural analyses have revealed that the N-terminal domain of NPC1L1 possesses a cavity that accommodates cholesterol (14–16).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [14] Hu M, Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake. Science Advances 7, eabg3188 (2021). 34272236 PMC8284890 source
The Introduction reports that the N-terminal domain binds cholesterol directly in vitro. It does not describe a cholesterol-accommodating cavity in that domain: the Results locate the observed cholesterol-filled cavity in the transmembrane sterol-sensing domain, and report that the N-terminal domain was not resolved in the authors’ structure. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [15] Huang C-S, Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition. Science Advances 6, eabb1989 (2020). 32596471 PMC7304964 source
- cites [16] Long T, Liu Y, Qin Y, DeBose-Boyd Russell A, Li X, Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption. Science Advances 7, eabh3997 (2021). 34407950 PMC8373123 source
The Introduction says that a mutation in NPC1L1’s N-terminal domain abolishes cholesterol binding. But the Results (Structures of hNPC1L1 with distinct lipid cargoes) say the N-terminal domain was not built into the structural models; the observed cholesterol-binding pocket is in the intramolecular channel, not a demonstrated N-terminal cavity. The paper therefore supports N-terminal involvement in binding, but not the claimed structural observation of a cavity there. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationNPC1 acts to enrich cholesterol in the lysosomal membrane.
“Molecular studies have established that NPC1 acts to enrich cholesterol in the lysosomal membrane (40, 41)”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [40] Kwon HJ, Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol. Cell 137, 1213– 1224 (2009). 19563754 PMC2739658 source
The paper’s Abstract proposes that transfer from NPC2 to NPC1 allows cholesterol to insert into the lysosomal membrane. The Discussion says this membrane-insertion model remains unproven; it does not establish that NPC1 enriches cholesterol in that membrane. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [41] Qian H, Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2. Cell 182, 98– 111.e118 (2020). 32544384 source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationBoth NPC1L1 and ACAT2 are key players in cholesterol absorption.
“both proteins are recognized to be key players in the process of cholesterol absorption (5, 6).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Zhang J, Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood[S]. Journal of Lipid Research 53, 1144– 1152 (2012). 22460046 PMC3351821 source
- cites [6] Altmann Scott W, Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303, 1201– 1204 (2004). 14976318
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationNPC1L1 is internalized when enterocytes are exposed to dietary cholesterol.
“Previous studies demonstrated that NPC1L1 is internalized when enterocytes are exposed to dietary cholesterol (38).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Xie C, Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. Journal of Lipid Research 53, 2092– 2101 (2012). 22811412 PMC3435542 source
It may state two separate claims as one.
Findingown dataLoss of NPC1L1 diminishes accessible plasma membrane cholesterol and abolishes Aster recruitment to the intestinal brush border.
“Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia.
“Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataEnterocytes lacking Asters accumulate plasma membrane cholesterol and show endoplasmic reticulum cholesterol depletion.
“Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum (ER) cholesterol depletion.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataRecruitment of HA-Aster-B to the apical plasma membrane of enteroids was induced by cholesterol loading in mixed micelles but reduced by ezetimibe.
“Immunofluorescence microscopy confirmed that recruitment of HA-Aster-B to the apical PM of enteroids was induced by cholesterol loading in MM but reduced by EZ (Fig. S9C).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataModeling of ezetimibe-glucuronide in the pocket suggested potential capacity for binding.
“Modeling of ezetimibe-glucuronide, the active metabolite of EZ, in the pocket suggested potential capacity for binding, since the glucuronide group is oriented toward an opening of the pocket (Fig. S8D).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe appearance of [14C]cholesterol in the plasma over time, as well as total plasma cholesterol levels, was reduced in I-B/C-KO mice.
“The appearance of [14C]cholesterol in the plasma over time, as well as total plasma cholesterol levels, was reduced in I-B/C-KO mice (Fig. 1L and 1M).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCircular dichroism spectra revealed that Aster-B and -C were thermally stabilized by ezetimibe binding, whereas Aster-A was not.
“Circular dichroism (CD) spectra of the Aster-A, -B, and -C domains revealed that Aster-B and -C were thermally stabilized by EZ binding, whereas Aster-A was not (Fig. S8E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIntestine-specific Aster-KO mice had lower fasting plasma cholesterol levels but no change in body weight.
“We also found lower fasting plasma cholesterol levels in intestine-specific Aster-KO mice but no change in body weight (Fig. 4D, E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCumulative counts in the proximal tract were reduced, while counts in medial and distal regions were not different in I-B/C-KO mice.
“Cumulative counts in the proximal tract (Fig. 1G) were reduced, while counts in medial and distal regions were not different (Fig. S3O, P).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataEzetimibe bound to Aster-B and Aster-C with moderate affinity, but exhibited minimal binding to Aster-A and StARD1.
“Using competition assays for 22-NBD-cholesterol binding, we found that EZ bound to Aster-B and Aster-C (Fig. 5A) with moderate affinity, but exhibited minimal binding to Aster-A and StARD1 (Fig. S8A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe thermal stability of the A357L Aster-C mutant did not change with ezetimibe binding, implying a weak interaction between ezetimibe and that mutant.
“The thermal stability of the A357L Aster-C mutant did not change with EZ binding, implying a weak interaction between EZ and that mutant (Fig. S8G).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTreatment of mice with a small-molecule Aster inhibitor reduces the systemic absorption of dietary cholesterol, and mice lacking Asters in the intestine are protected from diet-induced hypercholesterolemia.
“Treatment of mice with a small-molecule Aster inhibitor reduces the systemic absorption of dietary cholesterol, and mice lacking Asters in the intestine are protected from diet-induced hypercholesterolemia.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingown dataThe electron density map and simulated annealing composite omit map highlighted additional volume within the binding cavity that accommodates a glycerol molecule, and density for part of a PEG4000 molecule.
“The electron density map and the simulated annealing composite omit map highlighted additional volume within the binding cavity that accommodates a glycerol molecule, and density for part of a PEG4000 molecule from the cryo-protectant and crystallization buffer (Fig. S8B, S8C, respectively).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe Aster-A mutant L400A_F405I, as well as the single mutant L400A, reduced Aster-A thermal stability, but the stability was increased by ezetimibe.
“The Aster-A mutant L400A_F405I, as well as the single mutant L400A, reduced Aster-A thermal stability (Fig. S8G), but the stability was increased by EZ.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAsters are recruited to the enterocyte plasma membrane upon cholesterol loading, and loss of their expression impairs cholesteryl ester production.
“Asters are recruited to the enterocyte PM upon cholesterol loading, and loss of their expression impairs CE production.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLipidomic analyses revealed reduced cholesteryl ester in I-B/C-KO enterocytes on the high-cholesterol diet, without changes in other lipid species.
“Lipidomic analyses revealed reduced CE in I-B/C-KO enterocytes on the HC diet (Fig. 4J), without changes in other lipid species (Fig. S7C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAster-B/C-KO and I-B/C-KO mice showed decreased cholesteryl ester content and fractional cholesterol absorption; ezetimibe treatment led to a further reduction.
“Aster-B/C-KO and I-B/C-KO mice showed decreased CE content (Fig. 6A, B) and fractional cholesterol absorption (Fig. 6C); EZ treatment led to a further reduction.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDecreased ALOD4 staining was found in enteroids derived from NPC1L1-KO mice loaded with mixed micelle cholesterol, indicating that NPC1L1 is required to saturate the plasma membrane with accessible cholesterol.
“Furthermore, we found decreased ALOD4 staining in enteroids derived from NPC1L1-KO mice loaded with MM cholesterol, indicating that NPC1L1 is required to saturate the PM with accessible cholesterol (Fig. 6F, upper panels).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAster-C mutants A357L_I362F and A357L alone increased thermal stability of the protein, while I362F had no effect.
“These results were corroborated by the Aster-C mutants, where A357L_I362F and A357L alone increased thermal stability of the protein, while I362F had no effect.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe thermal stability upon ezetimibe binding was unchanged in the F405I mutant, suggesting that L400A is crucial for binding selectivity.
“The thermal stability upon EZ binding was unchanged in the F405I mutant (Fig. S8G), suggesting that L400A is crucial for binding selectivity.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataThe cavity is closed by a long carboxyl-terminal helix and two shorter helices.
“The cavity is closed by a long carboxyl-terminal helix and two shorter helices.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingown dataThe electron density for PEG is stronger at the end in proximity to the ezetimibe ligand and becomes weaker at the other end, presumably due to disorder.
“The electron density for the PEG is stronger at the end in proximity to the EZ ligand and becomes weaker at the other end, presumably due to disorder.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataLeucine 400 and phenylalanine 405 in the ASTER domain of Aster-A appeared to represent a steric hindrance to ezetimibe binding, while alanine 357 and isoleucine 362 in the ASTER domain of Aster-C left ample space for ezetimibe binding.
“However, leucine 400 and phenylalanine 405 in the ASTER domain of Aster-A appeared to represent a steric hindrance to EZ binding (Fig. 5D), while alanine 357 and isoleucine 362 in the ASTER domain of Aster-C left ample space for EZ binding (Fig. 5D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataUnlabeled cholesteryl ester species were lower, while unlabeled cholesterol was not different.
“Unlabeled CE species were also lower, while unlabeled cholesterol was not different (Fig. S6I, J).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThere was a marked reduction in 14C counts in the plasma of B/C-KO mice over 12 h, while B-KO and C-KO mice exhibited an intermediate phenotype.
“There was a marked reduction in 14C counts in the plasma of B/C-KO mice, while B-KO and C-KO mice exhibited an intermediate phenotype (Fig. 1K).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNo changes in body weight or lipid levels were observed in Aster single-KO mice after 21 days of high-cholesterol diet, nor was there a change in SREBP-2 targets.
“We did not observe changes in body weight (Fig. S7D) or lipid levels in Aster single-KO mice after 21 days of HC diet (Fig. S7 E and F), nor did we observe a change in SREBP-2 targets (Fig. S7G).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAI-3d did not affect body weight or intestinal length.
“AI-3d did not affect body weight or intestinal length (Fig. S10 F–H)”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
FindingcitationAI-3d reduced cholesterol transport to the ER and expanded the pool of accessible cholesterol at PM of intestinal enteroids.
“The inhibitor AI-3d, which had been shown previously (36) to inhibit Aster-mediated non-vesicular transport in vitro, reduced cholesterol transport to the ER and expanded the pool of accessible cholesterol at PM of intestinal enteroids.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Xiao X, Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms. Proceedings of the National Academy of Sciences 118, e2024149118 (2021). PMC7812747 33376205 source
It may state two separate claims as one.
Findingown dataFollowing cholesterol depletion, NPC1L1 partially localized to the plasma membrane, while Aster-B was confined to the ER.
“Following cholesterol depletion, NPC1L1 partially localized to PM, while Aster-B was confined to the ER (Fig. S9F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNPC1L1 deletion reduced 3×HA-Aster-B recruitment to the plasma membrane after mixed micelle cholesterol loading, but had no effect on MβCD cholesterol loading.
“In enteroids derived from these mice, NPC1L1 deletion reduced 3×HA-Aster-B recruitment to the PM after MM cholesterol loading, but had no effect on MβCD cholesterol loading (Fig. S9D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataMβCD-cholesterol loading caused internalization of NPC1L1-EGF and, concomitantly, the movement of HA-Aster-B to ER-PM contact sites.
“MβCD-cholesterol loading caused internalization of NPC1L1-EGF and, concomitantly, the movement of HA-Aster-B to ER-PM contact sites.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationThe intestine regulates systemic lipid homeostasis by gating dietary cholesterol intake.
“The intestine regulates systemic lipid homeostasis by gating dietary cholesterol intake (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Xie P, Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. Atherosclerosis 237, 609– 617 (2014). 25463095 PMC4262594 source
It may state two separate claims as one.
Interpretationown dataThese findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
“These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Study design and conductown dataMinimal differences in body weight or small intestine length were observed between control and I-B/C KO mice.
“Minimal differences in body weight or SI length were observed between control and I-B/C KO mice (Fig. S3H).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationEzetimibe was initially discovered as an inhibitor of ACAT2.
“EZ was initially discovered as an inhibitor of ACAT2 (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Clader JW, The Discovery of Ezetimibe: A View from Outside the Receptor. Journal of Medicinal Chemistry 47, 1– 9 (2004). 14695813 source
It may state two separate claims as one.
PremisecitationGenetic ablation of NPC1L1 or ezetimibe administration impairs cholesterol absorption.
“Genetic ablation of NPC1L1 or EZ administration impairs cholesterol absorption (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Altmann Scott W, Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303, 1201– 1204 (2004). 14976318
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataAster deficiency reduces cholesterol content in chylomicrons, but does not alter the process of chylomicron assembly and release per se.
“These findings suggest that Aster deficiency reduces cholesterol content in chylomicrons, but does not alter the process of chylomicron assembly and release per se.”
Quote in the paperSubstantial claim- Rests on an assumption: Adequate cholesteryl ester is required for chylomicron production by the intestine.
It may state two separate claims as one.
InterpretationreasoningThis enrichment facilitates the recruitment of Asters to the plasma membrane where they mediate non-vesicular cholesterol trafficking to the ER.
“This enrichment facilitates the recruitment of Asters to the PM where they mediate non-vesicular cholesterol trafficking to the ER.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationTreatment with ezetimibe protects mice from diet-induced hypercholesterolemia and atherosclerosis.
“Treatment with EZ protects mice from diet-induced hypercholesterolemia and atherosclerosis (1, 3, 12, 13).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [1] Xie P, Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. Atherosclerosis 237, 609– 617 (2014). 25463095 PMC4262594 source
Checked before — its earlier verdict is held back until a new check runs.
- cites [3] Buhman KK, Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nature Medicine 6, 1341– 1347 (2000). 11100118 source
- cites [12] Davis HR, Compton DS, Hoos L, Tetzloff G, Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Inhibits the Development of Atherosclerosis in ApoE Knockout Mice. Arteriosclerosis, Thrombosis, and Vascular Biology 21, 2032– 2038 (2001). 11742881 source
- cites [13] Lee RG, Plasma Cholesteryl Esters Provided by Lecithin:Cholesterol Acyltransferase and Acyl-Coenzyme A:Cholesterol Acyltransferase 2 Have Opposite Atherosclerotic Potential. Circulation Research 95, 998– 1004 (2004). 15486318 source
It may state two separate claims as one.
Interpretationown dataIntestinal Asters are key players in dietary lipid absorption and potential targets for the control of cholesterol homeostasis.
“These findings identify intestinal Asters as key players in dietary lipid absorption and potential targets for the control of cholesterol homeostasis.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Interpretationown dataThe precise translational position of the PEG is uncertain.
“Thus, the precise translational position of the PEG is uncertain.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataBody weight and intestinal length showed minimal differences across genotypes.
“The SI from B/C-KO mice had no obvious histological abnormalities (Fig. S2F), and body weight and intestinal length showed minimal differences across genotypes (Fig. S2G).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAster-C is important for hepatic reverse cholesterol transport.
“In mice, Aster-B is required for CE storage and corticosteroid synthesis in the adrenal cortex (25), while Aster-C is important for hepatic reverse cholesterol transport (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Xiao X, Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis. Nature Metabolism 5, 165– 181 (2023). PMC9995220 36646756 source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim.
PremisecitationNPC1L1 facilitates entry of cholesterol into enterocytes.
“The involvement of NPC1L1 in facilitating the entry of cholesterol into enterocytes”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Zhang J, Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood[S]. Journal of Lipid Research 53, 1144– 1152 (2012). 22460046 PMC3351821 source
Checked before — its earlier verdict is held back until a new check runs.
- cites [6] Altmann Scott W, Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303, 1201– 1204 (2004). 14976318
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper may give no reason why it holds.
Premisenone givenNPC1L1 is the gatekeeper that controls the first step of cholesterol uptake.
“Since NPC1L1 is the gatekeeper that controls the first step of cholesterol uptake”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningInhibition of Aster non-vesicular transport reduces cellular cholesterol stores and impairs the incorporation of CE into chylomicrons.
“Physiologically, inhibition of Aster non-vesicular transport reduces cellular cholesterol stores and impairs the incorporation of CE into chylomicrons.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationNPC1L1 is a homolog of the Niemann-Pick C1 (NPC1) protein that mediates cholesterol export from lysosomes following endocytosis of LDL cholesterol.
“NPC1L1 is a homolog of the Niemann-Pick C1 (NPC1) protein that mediates cholesterol export from lysosomes following endocytosis of LDL cholesterol (39).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Carstea ED, Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis. Science 277, 228– 231 (1997). 9211849 source
It may state two separate claims as one.
Interpretationown dataEzetimibe prevents the saturation of cholesterol at the apical membrane by inhibiting NPC1L1 rather than Aster-B inhibition.
“They further show that EZ prevents the saturation of cholesterol at the apical membrane by inhibiting NPC1L1 rather than Aster-B inhibition.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataAI-3d inhibits both human and murine Asters.
“indicating that AI-3d inhibits both human and murine Asters.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningThe structurally related NPC1 and NPC1L1 perform analogous functions: both enrich membrane cholesterol to facilitate the recruitment of non-vesicular transporters.
“Our results suggest that the structurally related NPC1 and NPC1L1 perform analogous functions: both enrich membrane cholesterol to facilitate the recruitment of non-vesicular transporters.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationSuch enrichment allows for the subsequent transfer of cholesterol to PM by cytoplasmic non-vesicular transfer proteins.
“and that such enrichment allows for the subsequent transfer of cholesterol to PM by cytoplasmic non-vesicular transfer proteins (42).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Wang H, ORP2 Delivers Cholesterol to the Plasma Membrane in Exchange for Phosphatidylinositol 4, 5-Bisphosphate (PI(4,5)P2). Molecular Cell 73, 458– 473.e457 (2019). 30581148 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationACAT2 is involved in cholesterol esterification.
“the role of ACAT2 in cholesterol esterification are well documented”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [5] Zhang J, Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood[S]. Journal of Lipid Research 53, 1144– 1152 (2012). 22460046 PMC3351821 source
Checked before — its earlier verdict is held back until a new check runs.
- cites [6] Altmann Scott W, Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 303, 1201– 1204 (2004). 14976318
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataCholesterol homeostasis in enterocytes requires both NPC1L1-mediated cholesterol deposition into the PM and subsequent Aster-mediated transport to the ER.
“Our results suggest that cholesterol homeostasis in enterocytes requires both NPC1L1-mediated cholesterol deposition into the PM and subsequent Aster-mediated transport to the ER.”
Quote in the paperSubstantial claim- The authors state this as an assumption: How cholesterol that enters the cell via NPC1L1 reaches the ER for esterification and regulation of cholesterol synthesis was a long-standing mystery.
The paper relies on this without support.
Intestinal absorption is an important contributor to systemic cholesterol homeostasis.
“Intestinal absorption is an important contributor to systemic cholesterol homeostasis.”
The paper relies on this without support.
Most cholesterol in chylomicrons is esterified, and cholesteryl ester is necessary for chylomicron packaging.
“Most of the cholesterol in chylomicrons is esterified, and cholesterol ester (CE) is necessary for chylomicron packaging.”
The paper relies on this without support.
The role of non-vesicular cholesterol transport in cell function is highly cell-type specific.
“The role of non-vesicular cholesterol transport in cell function is highly cell-type specific.”
The paper relies on this without support.
Adequate cholesteryl ester is required for chylomicron production by the intestine.
“Adequate CE is required for chylomicron production by the intestine.”
The paper relies on this without support.
Cholesterol moves through the NPC1L1 channel to diffuse into the lipid bilayer.
“Cholesterol moves through this channel to diffuse into the lipid bilayer.”
The authors state this as an assumption.
How cholesterol that enters the cell via NPC1L1 reaches the ER for esterification and regulation of cholesterol synthesis was a long-standing mystery.
“However, how cholesterol that enters the cell via NPC1L1 reaches the ER for esterification and regulation of cholesterol synthesis has been a long-standing mystery.”
The authors state this as an assumption.
Formal tests of the relative contribution of vesicular and non-vesicular cholesterol transport mechanisms downstream of NPC1L1 have been lacking.
“However, formal tests of the relative contribution of vesicular and non-vesicular cholesterol transport mechanisms downstream of NPC1L1 have been lacking.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GRAMD1B is a nonvesicular cholesterol transporter (Aster protein).
“GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [41]
Aster proteins, such as GRAMD1B, act at contact sites formed between the endoplasmic reticulum and the plasma membrane without membrane fusion.
“Aster proteins, such as GRAMD1B, act at contact sites formed between the endoplasmic reticulum and the plasma membrane without membrane fusion40,41.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [41]
Cholesterol accumulation can trigger compensatory regulatory mechanisms, including reducing cholesterol synthesis and enhancing bile acid synthesis, to eliminate high cholesterol levels and attempt to return the liver to a steady state.
“In general, cholesterol accumulation can trigger compensatory regulatory mechanisms, including reducing cholesterol synthesis and enhancing bile acid synthesis, to eliminate high cholesterol levels and attempt to return the liver to a steady state.85–88”
From EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis (2025) · cites this paper as [86]
Previous publications focus on the important role of GRAMD1B in the mouse periphery system such as the adrenal gland and the intestine.
“Previous publications focus on the important role of GRAMD1B in the mouse periphery system such as the adrenal gland40 and the intestine41.”
From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [41]
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
Trimmomatic: a flexible trimmer for Illumina sequence data
Bolger, A. M., Lohse, M., & Usadel, B. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu170 · Cited by 65,548
A SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
HTSeq—a Python framework to work with high-throughput sequencing data
Anders, S., Pyl, P. T., & Huber, W. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btu638 · Cited by 21,464
Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353
REFMAC 5 for the refinement of macromolecular crystal structures
Murshudov, G. N., Skubák, P., Lebedev, A. A., Pannu, N. S., Steiner, R. A., Nicholls, R. A., Winn, M., Long, F., & Vagin, A. A. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911001314 · Cited by 8,373
Liebschner, D., Afonine, P. V., Baker, M. L., Bunkóczi, G., Chen, V. B., Croll, T. I., Hintze, B., Hung, L.-W., Jain, S., McCoy, A. J., et al. (2019) · Acta Crystallographica Section D Structural Biology · doi:10.1107/s2059798319011471 · Cited by 7,953
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204
How good are my data and what is the resolution?
Evans, P. R., & Murshudov, G. N. (2013) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444913000061 · Cited by 4,713
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1410489 · Cited by 4,487
Globally optimal stitching of tiled 3D microscopic image acquisitions
Preibisch, S., Saalfeld, S., & Tomancak, P. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp184 · Cited by 2,452
Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption
Altmann, S. W., Davis, H. R., Zhu, L.-J., Yao, X., Hoos, L. M., Tetzloff, G. G., Iyer, S. P. N., Maguire, M., Golovko, A., Zeng, M., et al. (2004) · Science · doi:10.1126/science.1093131 · Cited by 1,818
Cellular cholesterol trafficking and compartmentalization
Ikonen, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2336 · Cited by 1,506
xia2 : an expert system for macromolecular crystallography data reduction
Winter, G. (2009) · Journal of Applied Crystallography · doi:10.1107/s0021889809045701 · Cited by 1,406
Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis
Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M. A., Pavan, W. J., Krizman, D. B., et al. (1997) · Science · doi:10.1126/science.277.5323.228 · Cited by 1,293
In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture
Miyoshi, H., & Stappenbeck, T. S. (2013) · Nature Protocols · doi:10.1038/nprot.2013.153 · Cited by 739
Liver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722
Self-citationThe target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)
Garcia-Calvo, M., Lisnock, J., Bull, H. G., Hawes, B. E., Burnett, D. A., Braun, M. P., Crona, J. H., Davis, H. R., Dean, D. C., Detmers, P. A., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500269102 · Cited by 670
Kwon, H. J., Abi-Mosleh, L., Wang, M. L., Deisenhofer, J., Goldstein, J. L., Brown, M. S., & Infante, R. E. (2009) · Cell · doi:10.1016/j.cell.2009.03.049 · Cited by 636
Davis, H. R., Zhu, L.-J., Hoos, L. M., Tetzloff, G., Maguire, M., Liu, J., Yao, X., Iyer, S. P. N., Lam, M.-H., Lund, E. G., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405817200 · Cited by 615
Gossert, A. D., Hinniger, A., Gutmann, S., Jahnke, W., Strauss, A., & Fernández, C. F. (2011) · Journal of Biomolecular NMR · doi:10.1007/s10858-011-9570-9 · Cited by 489
Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions
Co, J. Y., Margalef-Català, M., Li, X., Mah, A. T., Kuo, C. J., Monack, D. M., & Amieva, M. R. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.108 · Cited by 488
Liebisch, G., Binder, M., Schifferer, R., Langmann, T., Schulz, B., & Schmitz, G. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2005.12.007 · Cited by 454
Ge, L., Wang, J., Qi, W., Miao, H., Cao, J. P., Qu, Y.-X., Li, B.-L., & Song, B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.001 · Cited by 380
Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis
Das, A., Brown, M. S., Anderson, D. D., Goldstein, J. L., & Radhakrishnan, A. (2014) · eLife · doi:10.7554/elife.02882 · Cited by 354
The Discovery of Ezetimibe: A View from Outside the Receptor
Clader, J. W. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030283g · Cited by 325
Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice
Buhman, K. K., Accad, M., Novak, S., Choi, R. S., Wong, J. S., Hamilton, R. L., Turley, S., & Farese, R. V. (2000) · Nature Medicine · doi:10.1038/82153 · Cited by 312
Sandhu, J., Li, S., Fairall, L., Pfisterer, S. G., Gurnett, J. E., Xiao, X., Weston, T. A., Vashi, D., Ferrari, A., Orozco, J. L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.033 · Cited by 287
Self-citationThe Biogenesis of Chylomicrons
Mansbach, C. M., & Siddiqi, S. A. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135801 · Cited by 206
Expression of ABCG5 and ABCG8 Is Required for Regulation of Biliary Cholesterol Secretion
Yu, L., Gupta, S., Xu, F., Liverman, A. D. B., Moschetta, A., Mangelsdorf, D. J., Repa, J. J., Hobbs, H. H., & Cohen, J. C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411080200 · Cited by 192
Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2
Qian, H., Wu, X., Du, X., Yao, X., Zhao, X., Lee, J., Yang, H., & Yan, N. (2020) · Cell · doi:10.1016/j.cell.2020.05.020 · Cited by 185
Davis, H. R., Compton, D. S., Hoos, L., & Tetzloff, G. (2001) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/hq1201.100260 · Cited by 182
Wang, H., Ma, Q., Qi, Y., Dong, J., Du, X., Rae, J., Wang, J., Wu, W.-F., Brown, A. J., Parton, R. G., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.11.014 · Cited by 175
Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex
Naito, T., Ercan, B., Krshnan, L., Triebl, A., Koh, D. H. Z., Wei, F.-Y., Tomizawa, K., Torta, F. T., Wenk, M. R., & Saheki, Y. (2019) · eLife · doi:10.7554/elife.51401 · Cited by 171
A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption
Zhang, Y., Fu, Z.-Y., Wei, J. N., Qi, W., Baituola, G., Luo, J., Meng, Y. J., Guo, S., Yin, H., Jiang, S., et al. (2018) · Science · doi:10.1126/science.aao6575 · Cited by 163
Toll-Like Receptors Induce Signal-Specific Reprogramming of the Macrophage Lipidome
Hsieh, W.-Y., Zhou, Q., York, A. G., Williams, K. J., Scumpia, P. O., Kronenberger, E. B., Hoi, X. P., Su, B., Chi, X., Bui, V. L., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.003 · Cited by 161
Self-citationFlotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake
Ge, L., Qi, W., Wang, L.-J., Miao, H., Qu, Y.-X., Li, B.-L., & Song, B. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014434108 · Cited by 157
Su, B., Bettcher, L., Hsieh, W.-Y., Hornburg, D., Pearson, M. J., Blomberg, N., Giera, M. A., Snyder, M. P., Raftery, D., Bensinger, S. J., et al. (2021) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.1c00203 · Cited by 137
Self-citationWang, B., Rong, X., Duerr, M. A., Hermanson, D. J., Hedde, P. N., Wong, J. S., Vallim, T. Q. D. A., Cravatt, B. F., Gratton, E., Ford, D. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.001 · Cited by 129
Self-citationGRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
Besprozvannaya, M., Dickson, E., Li, H., Ginburg, K. S., Bers, D. M., Auwerx, J., & Nunnari, J. (2018) · eLife · doi:10.7554/elife.31019 · Cited by 128
Repa, J. J., Buhman, K. K., Farese, R. V., Dietschy, J. M., & Turley, S. D. (2004) · Hepatology · doi:10.1002/hep.20439 · Cited by 119
Extracellular loop C of NPC1L1 is important for binding to ezetimibe
Weinglass, A. B., Köhler, M. G., Schulte, U., Liu, J., Nketiah, E. O., Thomas, A., Schmalhofer, W. A., Williams, B. S., Bildl, W., McMasters, D. R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800936105 · Cited by 117
Lee, R. G., Kelley, K. L., Sawyer, J. K., Farese, R. V., Parks, J. S., & Rudel, L. L. (2004) · Circulation Research · doi:10.1161/01.res.0000147558.15554.67 · Cited by 107
Li, P., Fu, Z.-Y., Zhang, Y., Zhang, J., Xu, C., Ma, Y.-T., Li, B.-L., & Song, B. (2013) · Nature Medicine · doi:10.1038/nm.3417 · Cited by 106
Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition
Huang, C.-S., Yu, X., Fordstrom, P., Choi, K., Chung, B. C., Roh, S.-H., Chiu, W., Zhou, M., Min, X., & Wang, Z. (2020) · Science Advances · doi:10.1126/sciadv.abb1989 · Cited by 98
Nguyen, T. M., Sawyer, J. K., Kelley, K. L., Davis, M. A., & Rudel, L. L. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m018820 · Cited by 90
Switch-like Responses of Two Cholesterol Sensors Do Not Require Protein Oligomerization in Membranes
Gay, A., Rye, D., & Radhakrishnan, A. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.02.008 · Cited by 86
Davis, H. R., Pula, K. K., Alton, K. B., Burrier, R. E., & Watkins, R. W. (2001) · Metabolism · doi:10.1053/meta.2001.26737 · Cited by 79
Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake
Hu, M., Yang, F., Huang, Y., You, X., Liu, D., Sun, S., & Sui, S.-F. (2021) · Science Advances · doi:10.1126/sciadv.abg3188 · Cited by 72
He, C. H., Weston, T. A., Jung, R. S., Heizer, P. J., Larsson, M., Hu, X., Allan, C. M., Tontonoz, P., Reue, K., Beigneux, A. P., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.017 · Cited by 69
Self-citationVisual automated macromolecular model building
Langer, G. G., Hazledine, S., Wiegels, T., Carolan, C. G., & Lamzin, V. S. (2013) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444913000565 · Cited by 67
Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane
Ferrari, A., He, C., Kennelly, J. P., Sandhu, J., Xiao, X., Chi, X., Jiang, H., Young, S. G., & Tontonoz, P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00255-20 · Cited by 66
Self-citationChu, B., Ge, L., Xie, C., Zhao, Y., Miao, H., Wang, J., Li, B.-L., & Song, B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.034355 · Cited by 64
Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers
Wang, L., 王, 丽., Wang, J., 王, 婧., Li, N., 李, 钠., Ge, L., 葛, 亮., Li, B.-L., 李, 伯., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178368 · Cited by 64
Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine
Xie 谢畅, C., Zhou 周章森, Z.-S., Li 李钠, N., Bian 卞艳, Y., Wang 王永建, Y.-J., Wang 王丽娟, L.-J., Li 李伯良, B.-L., & Song 宋保亮, B.-L. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m027359 · Cited by 64
Blockade of cholesterol absorption by ezetimibe reveals a complex homeostatic network in enterocytes
Engelking, L. J., McFarlane, M., Li, C. K., & Liang, G. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m027599 · Cited by 60
Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis
Xu, X., Kennelly, J. P., Ferrari, A., Clifford, B. L., Whang, E. C., Gao, Y., Qian, K., Sandhu, J., Jarrett, K. E., Brearley-Sholto, M. C., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-022-00722-6 · Cited by 60
Self-citationAb initio solution of macromolecular crystal structures without direct methods
McCoy, A. J., Oeffner, R. D., Wrobel, A. G., Ojala, J. R. M., Tryggvason, K., Lohkamp, B., & Read, R. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1701640114 · Cited by 59
High-resolution imaging of dietary lipids in cells and tissues by NanoSIMS analysis
Jiang, H., Goulbourne, C. N., Tatar, A., Turlo, K. A., Wu, D. Y., Beigneux, A. P., Grovenor, C. R. M., Fong, L. G., & Young, S. G. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m053363 · Cited by 56
Self-citationEndapally, S., Infante, R. E., & Radhakrishnan, A. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9136-5_12 · Cited by 48
Iqbal, J., Boutjdir, M., Rudel, L. L., & Hussain, M. M. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m047951 · Cited by 47
Zhang, J., Kelley, K. L., Marshall, S. M., Davis, M. A., Wilson, M. D., Sawyer, J. K., Farese, R. V., Brown, J. M., & Rudel, L. L. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m024356 · Cited by 44
Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms
Xiao, X., Kim, Y., Romartinez-Alonso, B., Sirvydis, K., Ory, D. S., Schwabe, J. W. R., Jung, M. E., & Tontonoz, P. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2024149118 · Cited by 40
Self-citationStructures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption
Long, T., Liu, Y., Qin, Y., DeBose-Boyd, R. A., & Li, X. (2021) · Science Advances · doi:10.1126/sciadv.abh3997 · Cited by 36
Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis
Johnson, T. A., & Pfeffer, S. R. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-03-0154 · Cited by 35
Xie, P., Zhu, H., Jia, L., Ma, Y., Tang, W., Wang, Y., Xue, B., Shi, H., & Yu, L. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.09.036 · Cited by 24
Lee, S. D., Thornton, S. J., Sachs‐Barrable, K., Kim, J. H., & Wasan, K. M. (2013) · Molecular Pharmaceutics · doi:10.1021/mp4002415 · Cited by 10
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- 10.1128/mcb.00255-20 · DOI · Paper page
Cited by
Sorted by citations
Western diets and chronic diseases
Adolph, T. E., & Tilg, H. (2024) · Nature Medicine · doi:10.1038/s41591-024-03165-6 · Cited by 217
Cell membranes sustain phospholipid imbalance via cholesterol asymmetry
Doktorova, M., Symons, J. L., Zhang, X., Wang, H., Schlegel, J. A., Lorent, J. H., Heberle, F. A., Sezgin, E., Lyman, E. R., Levental, K. R., et al. (2023) · Cell · doi:10.1016/j.cell.2025.02.034 · Cited by 197
An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD
Zhang, L., Shi, Y., Liang, B., & Li, X. (2024) · Hepatology Communications · doi:10.1097/hc9.0000000000000434 · Cited by 48
EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis
Ma, F., Longo, M., Meroni, M., Bhattacharya, D., Paolini, E., Mughal, S., Hussain, S., Anand, S. K., Gupta, N., Zhu, Y., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.01.020 · Cited by 29
Nonvesicular cholesterol transport in physiology
Ferrari, A., & Tontonoz, P. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188127 · Cited by 25
Self-citationThe Role of Cholesterol Metabolism and Its Regulation in Tumor Development
Wu, Y., Song, W., Su, M., He, J., Hu, R., & Zhao, Y. (2025) · Cancer Medicine · doi:10.1002/cam4.70783 · Cited by 23
Self-citationT cell cholesterol transport links intestinal immune responses to dietary lipid absorption
Gao, Y., Kennelly, J. P., Xu, X., Whang, E. C., Ferrari, A., Bedard, A. H., Mack, J. J., Nguyen, A., Srikanth, S., Weston, T. A., et al. (2025) · Science · doi:10.1126/science.adt4169 · Cited by 19
Self-citationPhotosensitizer proximity labeling captures the lipid and protein interactomes
Becker, A. P., Biletch, E., Kennelly, J. P., Hong, S., Julio, A. R., Villanueva, M., Nagari, R. T., Turner, D. W., Burton, N. R., Fukuta, T., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-026-02140-1 · Cited by 18
Self-citationBalancing cholesterol metabolism in the liver and gut: perspectives in health and disease
Yamauchi, Y., Sharpe, L. J., & Brown, A. J. (2026) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01168-3 · Cited by 15
The Absorption, Storage, and Transport of Ocular Carotenoids and Retinoids
Lintig, J. V., & Bandara, S. (2024) · Annual Review of Vision Science · doi:10.1146/annurev-vision-102122-101846 · Cited by 15
Bandara, S., Saadane, A., Shen, T., Yakovleva, D., Banerjee, R., Zhang, Y., Brown, J. M., & Lintig, J. V. (2025) · Journal of Lipid Research · doi:10.1016/j.jlr.2025.100758 · Cited by 13
GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau
Acosta Ingram, D., Turkes, E., Kim, T. Y., Vo, S., Sweeney, N., Bonte, M.-A., Rutherford, R., Julian, D. L., Pan, M., Marsh, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58585-w · Cited by 12
How active cholesterol coordinates cell cholesterol homeostasis: Test of a hypothesis
Lange, Y., & Steck, T. L. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101304 · Cited by 11
Li, X., Huang, X., Song, K., Liu, J., Jin, Y., Li, T., Zhang, L., & Zhang, H. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156691 · Cited by 9
Evidence further linking the intestine to cardiovascular disease
Sulaiman, D., Reddy, S. T., & Fogelman, A. M. (2024) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000944 · Cited by 9
Chen, Y., Xiao, T., & Kimbrough, A. (2024) · Psychopharmacology · doi:10.1007/s00213-024-06739-x · Cited by 8
Wang, S., Li, B., Tan, H., Sun, X., Tian, J., Li, S., Xu, Y., Bian, Y., & Wang, Y. (2024) · Food Frontiers · doi:10.1002/fft2.482 · Cited by 8
The Gut Microbiome Affects Atherosclerosis by Regulating Reverse Cholesterol Transport
Jiang, Y., Pang, S., Liu, X., Wang, L., & Liu, Y. (2024) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-024-10480-3 · Cited by 8
Li, B., Chang, F., Wan, Z., Giauque, N. A., Addo, E. K., & Bernstein, P. S. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110043 · Cited by 7
Calvo, C., Swoboda, C. O., Montecino, F., Nagar, S., Petrany, M. J., Sun, C., Durumutla, H. B., Quattrocelli, M., & Millay, D. P. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2424246122 · Cited by 6
Recent advances in carotenoid absorption, distribution, and elimination
Hajeer, W., Blanco, A., Miller, A. P., & Amengual, J. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2025.159619 · Cited by 5
Using GRAM Domain–Based Biosensors to Monitor Accessible Cholesterol Distribution in Live Cells
Naito, T., Na, M., Koh, D. H. Z., & Saheki, Y. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-4318-1_6 · Cited by 5
A (cholesterol) crystal clear path to inflammasome activation in atherosclerosis
Li, X., & Sallam, T. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100554 · Cited by 5
The contribution of mitochondria-associated ER membranes to cholesterol homeostasisPreprint
Montesinos, J., Kabra, K., Uceda, M., Larrea, D., Agrawal, R. R., Tamucci, K. A., Pera, M., Ferre, A. C., Gomez‐Lopez, N., Yun, T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.11.622945 · Cited by 5
Sun, Y. X., Yan, K., Zhang, Y., Han, Y., Hao, L.-H., Gao, Y., Wang, H., Chu, H., Ye, J., Liu, Y., et al. (2025) · Military Medical Research · doi:10.1186/s40779-025-00672-6 · Cited by 4
Self-citationThe nonvesicular sterol transporter Aster-C plays a minor role in whole body cholesterol balance
Banerjee, R., Hohe, R. C., Cao, S., Jung, B. M., Horak, A. J., Ramachandiran, I., Massey, W. J., Varadharajan, V., Zajczenko, N., Burrows, A. C., et al. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1371096 · Cited by 4
Cholesterol binding to VCAM-1 promotes vascular inflammationPreprint
Kennelly, J. P., Xu, X., Gao, Y., Kim, S. M., Hong, S., Villanueva, M., Ferrari, A., Vanharanta, L., Nguyen, A., Nagari, R. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.17.613543 · Cited by 4
Self-citationZhou, Z.-H., Zong, J., & Xu, N. (2025) · Analytical Sciences · doi:10.1007/s44211-025-00842-5 · Cited by 3
Wijesinghe, K. M., Kim, C.-W., Chen, S., Schad, E. O., Takeshima, E., Li, S., Khandwala, C. B., Calhoon, D., Danielewicz, M., Leib, R. D., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-78470-4 · Cited by 3
Mitochondrial dysfunction in lipid processing and gastrointestinal disorders
Hu, Y. P., Huang, H., & Xiang, R. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.02.009 · Cited by 3
From Genetic Findings to new Intestinal Molecular Targets in Lipid Metabolism
May, C. L., Ducheix, S., Cariou, B., & Rimbert, A. (2025) · Current Atherosclerosis Reports · doi:10.1007/s11883-024-01264-w · Cited by 3
Mechanism and therapeutic potential of liver injury induced by cholesterol-associated proteins
Zhou, Y., Cao, Y., Yin, Y., Xu, Z., Yang, X., Yang, B., Luo, P., Yan, H., & He, Q.-J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1572592 · Cited by 3
Wen, X., Wang, J., Sun, J., Jin, Z., Li, Q., Wang, G., Zhao, J., Wang, Z., & Tian, P. (2025) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.70251 · Cited by 2
Jiang, Q. L., Tang, Y.-X., & Zhou, G. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115457 · Cited by 2
Xiao, F. N., Norris, D. M., Yang, G., Li, Y. E., Brown, A. J., & Yang, H. (2026) · Journal of Lipid Research · doi:10.1016/j.jlr.2026.100989 · Cited by 2
Zumaraga, M. P., Borel, P., & Desmarchelier, C. (2026) · Food & Function · doi:10.1039/d5fo05171a · Cited by 2
Huang, J., Ma, K., Ding, S., Wang, Y., Xiong, J., Yi, J., Zhang, J., He, Z. F., Huang, L., Ren, X., et al. (2026) · Emerging Microbes & Infections · doi:10.1080/22221751.2026.2651464 · Cited by 2
Chen, P.-Y., Liou, J.-W., Wu, M., & Yen, J.-H. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48060592 · Cited by 2
Shen, C., Bandara, S., Imanishi, S. S., Kalra, M., Imanishi, Y., & Lintig, J. V. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2025.159600 · Cited by 2
METTL3 promotes the hypertrophic scar fibrosis via m6A RNA methylation of GRAMD1B mRNA
Guo, W., Song, W., Zhai, Y., Bai, P., Guo, Z., Tian, X., & Duan, P. (2025) · Journal of Molecular Histology · doi:10.1007/s10735-025-10475-7 · Cited by 2
Self-citationZhang, J., Li, X., Li, D.-X., Zhang, Z.-H., Hu, L., Sun, C.-X., Zhang, X., Wu, M., & Liu, L. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117720 · Cited by 1
Aster-B Modulates Oxidative Stress Responses and Carotenoid Distribution in ARPE-19 Cells
Gopakumar, V., & Lintig, J. V. (2025) · Antioxidants · doi:10.3390/antiox14050575 · Cited by 1
Anserine alleviates atherosclerosis in ApoE −/− mice by regulating lipid metabolism
Luo, J., Chen, M., Ji, H., Zhang, D., Su, W., & Liu, S. (2025) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.70092 · Cited by 1
Rodríguez-Rojas, L. A., Bucio, L., Souza-Arroyo, V., Gutiérrez‐Ruíz, M. C., Gómez-Quiroz, L. E., & Miranda-Labra, R. U. (2025) · Exploration of Digestive Diseases · doi:10.37349/edd.2025.100583 · Cited by 1
New insights into dietary cholesterol absorption
Harman, J. J. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00975-y · Cited by 1
(2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23565-8.09996-8
Illness Comorbidities in Relation to Inflammatory Processes
Anisman, H., Hayley, S. P., & Kusnecov, A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23565-8.00003-x
Strategies to Overcome Metabolic Syndrome and Related Diseases
(2025) · Frontiers research topics · doi:10.3389/978-2-8325-5556-9
Bentley, A. R., Brown, M. R., Musani, S. K., Schwander, K., Winkler, T. W., Sims, M., Kilpeläinen, T. O., Aschard, H., Bartz, T. M., Bielak, L. F., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03418-z
Wan, J., Zhang, Y., Ge, N., Guan, H., & Liu, J. (2025) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2025.106833
Guan, X., Liu, Y., Huang, K., Zhang, Y., Li, S., Liu, J., Song, H., Zhang, Y., Cao, H., Chen, J., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-7956394/v1
Use of small unilamellar vesicles to study the biochemical properties of the GRAM domain of GRAMD1
Koh, D. H. Z., & Saheki, Y. (2025) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2025.11.014
Zhu, H., Zhang, Z., Wang, J., Wang, Z., Luo, Z., Duan, B., & Wu, J. (2026) · FEBS Journal · doi:10.1111/febs.70506
Wu, X., Liang, W., He, S., Chen, G., Zhou, H., Wang, X., Li, Y., Wu, D., Zheng, B., Dou, R., et al. (2026) · Advanced Science · doi:10.1002/advs.75362
Berthomé, A., Vairo, D., Chotard, M., Desmarchelier, C., Zumaraga, M. P., Borel, P., Bravo‐Núñez, Á., Sabran, C., Sirvins, C., & Reboul, E. (2026) · Research Square · doi:10.21203/rs.3.rs-9607215/v1
STING is a novel channel to facilitate cholesterol loading into Endoplasmic Reticulum membranePreprint
Wang, C., Maimaiti, M., Mei, J., Xu, Y., Zhong, Z., Ma, X., Li, C., Sun, C., Hu, H., & Hong, Z. (2026) · Research Square · doi:10.21203/rs.3.rs-10064343/v1
Cholesterol metabolism reprogramming: shaping tumor immunity and immunotherapy
Meng, J.-W., Tan, Y.-T., Chen, S.-M., Li, T., & Wang, H. (2026) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-026-03791-7
Free Fatty Acids Carried by Lipoproteins: Revisiting the Overlooked Cargo
Henderson, G. C., Buhman, K. K., & Tomoo, K. (2026) · Acta Physiologica · doi:10.1111/apha.70296
Design and structural basis of selective nonsteroidal inhibitors of aster cholesterol trafficking
Kim, H., Romartínez-Alonso, B., Xiao, X., Gao, Y., Kennelly, J. P., Ferrari, A., Li, R., Cui, L., Whang, E. C., Schwabe, J. W. R., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2617638123
Self-citationYamanashi, Y., Kitani, M., Kumamaru, M., Fukaya, T., Sugita, R., & Takada, T. (2026) · iScience · doi:10.1016/j.isci.2026.117625
Cholesterol Absorption: Mechanisms, Regulation, and Therapeutic Targets
Abdalqadir, N., & Adeli, K. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-27658-3.00059-7
Metadata
- Authors
- Ferrari, A., Whang, E., Xiao, X., Kennelly, J. P., Romartinez-Alonso, B., Mack, J. J., Weston, T., Chen, K., Kim, Y., Tol, M. J., Bideyan, L., Nguyen, A., Gao, Y., Cui, L., Bedard, A. H., Sandhu, J., Lee, S. D., Fairall, L., Williams, K. J., Song, W., Munguia, P., Russell, R. A., Martin, M. G., Jung, M. E., Jiang, H., Schwabe, J. W. R., Young, S. G., & Tontonoz, P.
- Affiliations
- University of California, Los Angeles (US)
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
- Institute for Structural and Chemical Biology, University of Leicester, Leicester LE1 7RH, UK.
- The University of Western Australia (AU)
- Department of Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
- University of Leicester (GB)
- Australian Nuclear Science and Technology Organisation (AU)
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
- Corresponding author
- Tontonoz, Peter
- ORCID
- Ferrari, Alessandra
- Whang, Emily
- Xiao, Xu
- Kennelly, John P.
- Romartinez-Alonso, Beatriz
- Mack, Julia J.
- Weston, Thomas
- Chen, Kai
- Kim, Youngjae
- Bideyan, Lara
- Nguyen, Alexander
- Gao, Yajing
- Cui, Liujuan
- Bedard, Alexander H.
- Sandhu, Jaspreet
- Lee, Stephen D.
- Fairall, Louise
- Williams, Kevin J.
- Song, Wenxin
- Russell, Robert A.
- Martin, Martin G.
- Jung, Michael E.
- Jiang, Haibo
- Schwabe, John W. R.
- Young, Stephen G.
- Tontonoz, Peter
- Venue
- Science
- Published
- 2023-11-10
- Volume
- 382
- Issue
- 6671
- Pages
- eadf0966-eadf0966
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC11073449
- OpenAlex
- W4388520069
- Cited by
- 61
- References
- 70
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 18 · 2023: 2
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- PubMed Central (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- The Australian Nuclear Science and Technology Organisation Institutional Repository (The Australian Nuclear Science and Technology Organisation) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion, cc-by-nc-nd)
- Funders
- American Diabetes Association
- American Heart Association (18POST34030388, 903306)
- Damon Runyon Cancer Research Foundation
- Australian Government
- UCSD-UCLA Diabetes Research Center
- Fondation Leducq (19CDV04)
- Wuhan University
- National Institutes of Health (NIH K12, DK063491)
- University of California, San Diego (DK063491)
- National Heart, Lung, and Blood Institute (P01HL146358, R35HL139725)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126779, T32DK007180, P30DK063491, RC2DK118640)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD111040)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- dietary cholesterol absorption, NPC1L1, ezetimibe, ACAT2, enterocytes, intestinal brush border, endoplasmic reticulum cholesterol, SREBP2, diet-induced hypercholesterolemia, small molecule inhibitors, cholesterol homeostasis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
