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Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol
Open accessAbstract
High serum cholesterol (hypercholesterolemia) strongly associates with cardiovascular diseases as the atherogenic LDLs promote atheroma development in arteries (atherosclerosis). LDL clearance from the circulation by LDL receptor (LDLR)-mediated endocytosis by hepatic and peripheral tissues and subsequent feedback regulation of endogenous synthesis of cholesterol is a key determinant of serum LDL level. Human mutation analysis revealed that autosomal recessive hypercholesterolemia (ARH), an LDLR endocytic adaptor, perturbs LDLR function and thus impacts serum cholesterol levels. In our genetic analysis of mutant mice, we found that deletion of another LDLR endocytic adaptor, Disabled-2 (Dab2), only slightly affected serum cholesterol levels. However, elimination of both arh and dab2 genes in mice resulted in profound hypercholesterolemia similar to that resulting from ldlr homozygous deletion. In the liver, Dab2 is expressed in sinusoid endothelial cells but not in hepatocytes. When deleting both Dab2 and Arh, HMG-CoA reductase level increased to the level similar to that of ldlr knockout. Thus, in the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis in hepatocytes. We conclude that the combination of Arh and Dab2 is responsible for the majority of adaptor function in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.
Overview
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Written from the paper’s full text.
TL;DR
Deleting both endocytic adaptors Arh and Dab2 in mice reproduces the hypercholesterolemia and elevated hepatic HMG-CoA reductase seen in LDL receptor knockout mice, whereas loss of Dab2 alone has only a minor effect. The authors conclude that Arh and Dab2 together account for most LDLR endocytic adaptor function in circulatory cholesterol homeostasis, with Dab2 acting in liver sinusoidal endothelial cells rather than hepatocytes.
Key findings
- Arh knockout mice have substantially increased circulatory cholesterol but ~30% lower than ldlr knockout mice; Dab2-null mice show only a small increase in serum cholesterol.
- Dab2/Arh double-knockout mice had serum cholesterol elevated to a level similar to LDLR knockout, reflecting combined increases in LDL, HDL, and VLDL; serum triglyceride also rose but not to the LDLR-knockout level, and liver cholesterol accumulation was quantitatively comparable to LDLR knockout.
- Hepatic HMG-CoA reductase (HMGCR) was greatly increased in Arh/Dab2 double-knockout liver, comparable to LDLR knockout, indicating unsuppressed cholesterol synthesis.
- In MEFs, Dab2- or Arh-null cells showed significantly reduced BODIPY-LDL uptake, and double-knockout cells had little uptake, similar to LDLR-null cells; only ~30% of MEFs were Dab2-positive, and cells positive for either Dab2 and/or Arh took up LDL similarly.
- Dab2 was expressed in liver sinusoidal endothelial cells (staining resembling PECAM-1/CD31) but not in hepatocytes or Kupffer cells (F4/80 pattern dissimilar), while most liver LDLR localized to hepatocytes.
Methods
- Mouse genetics: dab2 floxed conditional knockout crossed with Sox2-Cre and arh (−/−) mice to generate Dab2/Arh double knockouts; arh (B6;129S-Ldlrap1tm1Her/J) and ldlr (B6.129S7-Ldlrtm1Her/J) knockouts from Jackson Lab; dab2 heterozygous siblings used as controls.
- Mice were maintained on 5K20 chow or a high-sucrose diet (60.2% sucrose, <0.2% fat) for 3 months to induce hypercholesterolemia; serum lipids measured on a Vitros 250 analyzer with LDL/VLDL estimated by formula, and liver cholesterol extracted by the Folch method and analyzed by LC/MS.
- Cell and molecular assays: primary MEFs for BODIPY-labeled human LDL (25 μg/ml) uptake imaging, Western blots (Dab2, Arh, LDLR, HMGCR, adaptin α, β-actin), immunofluorescence microscopy of liver sections, and quantitative RT-PCR for LDLR/VLDLR normalized to GAPDH.
Limitations
- Stated by the paper: the study was limited to animals on a high-sucrose diet in the absence of dietary cholesterol, and the authors note the mechanism would be expected to be more intricate with a high-fat, exogenous-cholesterol diet.
- Stated by the paper: it was uncertain whether the higher-molecular-mass Arh variant seen in MEFs relates to posttranslational modifications such as S-nitrosylation, and the apparent transcriptional regulatory network between receptors and adaptors "warrants future investigation."
- Evident from the text: several conclusions rest on qualitative or semi-quantitative Western blot and immunofluorescence comparisons (e.g., HMGCR levels "comparable to" LDLR knockout) rather than reported quantitative values, and the LDL-uptake assay used MEFs rather than liver cells, so the hepatocyte-versus-endothelial division of labor is inferred rather than directly tested.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
10 of 34 cited sources checked · 4 supported · 1 flagged · accuracy not yet measured
- Premisecitation§ Abstract
LDL clearance from the circulation by LDLR-mediated endocytosis by hepatic and peripheral tissues and subsequent feedback regulation of endogenous synthesis of cholesterol is a key determinant of serum LDL level.
“LDL clearance from the circulation by LDL receptor (LDLR)-mediated endocytosis by hepatic and peripheral tissues and subsequent feedback regulation of endogenous synthesis of cholesterol is a key determinant of serum LDL level”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Brown, 1984, How LDL receptors influence cholesterol and atherosclerosis, Sci. Am. source
- cites [7] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
- cites [8] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J. Clin. Invest. source
The study summary (page not specified in our copy) reports that LDLR accounted for most LDL-cholesterol turnover in mice and that deleting it sharply raised plasma LDL-cholesterol. But most receptor-dependent transport occurred in the liver, and cholesterol synthesis did not change in extrahepatic organs or the whole animal. The claim's emphasis on peripheral clearance and subsequent feedback regulation of synthesis is therefore not supported by these findings. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation§ Abstract
Serum cholesterol is much higher in LDLR-null than in arh-deleted mice.
“serum cholesterol is much higher in LDLR-null than in arh-deleted mice”
Quote in the paperSubstantial claim1 of 4 sources checked- cites [19] Jones, 2003, Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia, J. Biol. Chem. source
The Results report much higher plasma cholesterol in LDLR-null mice than in Arh-deleted mice on a chow diet (196 versus 83 mg/dl). The claim omits that diet qualification: levels were similar on the Western diet and closer on the Paigen diet. (LLM, conf=0.89)
Experimental — accuracy not yet measured - cites [20] Jones, 2007, Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia, J. Clin. Invest. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [21] Harada-Shiba, 2004, Disruption of autosomal recessive hypercholesterolemia gene shows different phenotype in vitro and in vivo, Circ. Res. source
- cites [25] Ishibashi, 1993, Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery, J. Clin. Invest. source
Checked before — its earlier verdict is held back until a new check runs.
- Premisecitation§ Abstract
Conventional dab2 gene deletion in mice results in early embryonic death.
“Conventional dab2 gene deletion in mice results in early embryonic death”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [26] Yang, 2002, Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis, Dev. Biol. source
- cites [27] Morris, 2002, Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport, EMBO J. source
- cites [28] Yang, 2007, Disabled-2 is an epithelial surface positioning gene, J. Biol. Chem. source
- Premisecitation§ Abstract
Excessive cholesterol in the circulation, upon uptake by the liver via LDLR-mediated endocytosis, suppresses endogenous synthesis of cholesterol in the liver.
“Excessive cholesterol in the circulation, upon uptake by the liver via LDL receptor (LDLR)-mediated endocytosis, suppresses endogenous synthesis of cholesterol in the liver”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] Brown, 1984, How LDL receptors influence cholesterol and atherosclerosis, Sci. Am. source
- cites [7] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
- cites [8] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J. Clin. Invest. source
The study summary (section and page unavailable in our copy) reports that most LDL cholesterol returns to the liver and that the LDL receptor accounts for most receptor-dependent transport. It does not report that this uptake suppresses cholesterol synthesis in the liver; it reports no change in whole-animal synthesis after LDLR deletion, which does not settle the liver-specific effect. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data§ RESULTS
Arh and Dab2 double-knockout cells had little ability to uptake LDL, of a level similar to that of LDLR null.
“Remarkably, the Arh and Dab2 double-knockout cells had little ability to uptake LDL, of a level similar to that of LDLR null (Fig. 4).”
Quote in the paperSubstantial claim
- Findingown data§ RESULTS
On high-sucrose diet, mice with dab2 deletion gained less body weight than dab2 heterozygous.
“However, on high-sucrose diet, mice with dab2 deletion gained less body weight than dab2 heterozygous (Fig. 3A).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
In MEFs, Arh-null cells have increased LDLR mRNA.
“In MEFs, we also observed an increased LDLR mRNA in Arh-null cells and reduced VLDLR upon dab2 deletion (Fig. 2D).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
Dab2 gene ablation alone in mice has a relatively minor impact on serum cholesterol.
“Dab2 gene ablation alone in mice has a relatively minor impact on serum cholesterol, and the results suggest that Arh is the main LDLR endocytic adaptor involved in the clearance of circulating LDL in both liver and extrahepatic tissues and in the regulation of HMGCR for cholesterol synthesis.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
dab2 and arh double-knockout mice had serum cholesterol elevated to a level similar to that of the LDLR knockout.
“We found that the dab2 and arh double-knockout mice had serum cholesterol elevated to a level similar to that of the LDLR knockout (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The concentrated and punctate LDLR staining near the sinusoidal edge did not overlap with PECAM staining that marks the sinusoidal endothelial cells.
“At a greater magnification, the concentrated and punctate LDLR staining near the sinusoidal edge did not overlap with PECAM staining that marks the sinusoidal endothelial cells, as examples indicated by arrows (Fig. 7A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The Dab2 signal appeared localized to most, but not all, endothelial cells in the liver.
“Under higher magnification (Fig. 6A), the Dab2 signal appeared localized to most, but not all, endothelial cells in the liver.”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Compared with dab2 (+/−) cells, Dab2- or Arh-null cells had significantly reduced ability to uptake LDL particles.
“Compared with dab2 (+/−) cells, Dab2- or Arh-null cells had significant reduced ability to uptake LDL particles (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Only cells negative for both Dab2 and Arh remained unlabeled.
“Thus, cells positive for either Dab2 and/or Arh are sufficient to support LDLR-mediated uptake of BODIPY-labeled LDL and were fluorescently labeled to a similar extent; only the cells negative for both Dab2 and Arh remained unlabeled.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Elimination of both arh and dab2 genes in mice resulted in profound hypercholesterolemia similar to that resulting from ldlr homozygous deletion.
“elimination of both arh and dab2 genes in mice resulted in profound hypercholesterolemia similar to that resulting from ldlr homozygous deletion”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The pattern of Dab2 staining by immunofluorescence microscopy resembles that of PECAM-1 (CD31), a marker of liver sinusoidal endothelial cells.
“The pattern of Dab2 staining by immunofluorescence microscopy resembles that of PECAM-1, also noted as CD31, a marker of liver sinusoidal endothelial cells (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Dab2 staining is distinct from the intense LDLR signals near the sinusoidal edge.
“Similarly, Dab2 staining is distinct from the intense LDLR signals near the sinusoidal edge (Fig. 7B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Increased accumulation of cholesterol in the livers of the double-knockout mice was quantitatively comparable to those of LDLR knockout.
“Increased accumulation of cholesterol in the livers of the double-knockout mice was also found quantitatively comparable to those of LDLR knockout (Fig. 3C).”
Quote in the paperSubstantial claim - Findingnone given§ RESULTS
On a normal chow diet, there were no noticeable differences between the body weights of wild-type, mutant, and double-knockout mice.
“On a normal chow diet, there were no noticeable differences between the body weights of wild-type, mutant, and double-knockout mice.”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
Dab2 knockout animals have a significant increase in liver cholesterol content.
“Nevertheless, we did observe a significant increase in liver cholesterol content in Dab2 knockout animals, suggesting that Dab2 does impact LDL uptake through the liver sinusoidal endothelial cells and cholesterol synthesis despite the presence of Arh.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Dab2 protein is much lower in the liver compared with other tissues analyzed.
“The presence of proteins were validated by Western blot of tissues obtained from experimental mice, and the results indicate that LDLR and Arh proteins are indeed abundant in liver, whereas Dab2 is much lower in the liver compared with other tissues analyzed (Fig. 1B).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Dab2 is not expressed in hepatocytes.
“Surprisingly, Dab2 is not expressed in hepatocytes.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Partial overlapping of Dab2 and LDLR signals was observable.
“However, partial overlapping of Dab2 and LDLR signals was observable (Fig. 7B, arrows).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Elimination of Dab2 or LDLR elicited a compensatory increase in Arh protein in MEFs.
“Elimination of Dab2 or LDLR elicited a compensatory increase in Arh protein in MEFs (Fig. 2B) but not in liver tissues (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Dab2 expression is much lower in magnitude in other tissues including the liver.
“In comparison, Dab2 is expressed highly in several tissues and cell types including macrophages, kidney, white adipose, adrenal, lactating mammary glands; however, the expression, although present widely, is much lower in magnitude in other tissues including the liver (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
The two immunofluorescent signals (Dab2 and F4/80) were often seen adjacent but not colocalized.
“The staining patterns were clearly dissimilar between Dab2 and F4/80 in the same section, and the two immunofluorescent signals were often seen adjacent but not colocalized (Fig. 6C), suggesting that Dab2 is not expressed in Kupffer cells.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Arh and Dab2 double-knockout liver tissues had a greatly increased HMGCR level, comparable to that of LDLR knockouts.
“Arh and Dab2 double-knockout liver tissues had a greatly increased HMGCR level, comparable to that of LDLR knockouts (Fig. 5).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
In MEFs, dab2 deletion reduces VLDLR.
“In MEFs, we also observed an increased LDLR mRNA in Arh-null cells and reduced VLDLR upon dab2 deletion (Fig. 2D).”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
When deleting both Dab2 and Arh, HMG-CoA reductase level increased to a level similar to that of ldlr knockout.
“When deleting both Dab2 and Arh, HMG-CoA reductase level increased to the level similar to that of ldlr knockout”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Deletion of the LDLR endocytic adaptor Dab2 in mice only slightly affected serum cholesterol levels.
“deletion of another LDLR endocytic adaptor, Disabled-2 (Dab2), only slightly affected serum cholesterol levels”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The high serum cholesterol in the double-knockout mice appears to be a combination of increased cholesterol in LDL, HDL, and VLDL.
“The high serum cholesterol in the double-knockout mice appears to be a combination of increased cholesterol in LDL, HDL, and VLDL (Fig. 3B).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
arh deletion did not cause a compensatory expression of Dab2 or LDLR proteins in either MEFs or hepatic tissues.
“In contrast, arh deletion did not cause a compensatory expression of Dab2 or LDLR proteins in either MEFs or hepatic tissues (Fig. 2B, C).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
The staining patterns were clearly dissimilar between Dab2 and F4/80 in the same section.
“The staining patterns were clearly dissimilar between Dab2 and F4/80 in the same section, and the two immunofluorescent signals were often seen adjacent but not colocalized (Fig. 6C), suggesting that Dab2 is not expressed in Kupffer cells.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Dab2 is expressed highly in several tissues and cell types including macrophages, kidney, white adipose, adrenal, lactating mammary glands.
“In comparison, Dab2 is expressed highly in several tissues and cell types including macrophages, kidney, white adipose, adrenal, lactating mammary glands; however, the expression, although present widely, is much lower in magnitude in other tissues including the liver (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
Double knockout of the endocytic adaptors Arh and Dab2 mirrored the phenotypes of the LDLR knockout, in the similar elevated level of circulating and liver cholesterol and increased hepatic HMGCR.
“The experiments described in this study show that double knockout of the endocytic adaptors Arh and Dab2 mirrored the phenotypes of the LDLR knockout, in the similar elevated level of circulating and liver cholesterol and increased hepatic HMGCR.”
Quote in the paperSubstantial claim - Findingnone given§ Abstract
In the liver, Dab2 is expressed in sinusoid endothelial cells but not in hepatocytes.
“In the liver, Dab2 is expressed in sinusoid endothelial cells but not in hepatocytes”
Quote in the paperSubstantial claim - Study design and conductown data§ RESULTS
Dab2 and Arh proteins are completely absent in the compound mutant mice.
“Western blot analysis of MEFs and liver tissues derived from the control and mutant mice confirmed the complete absence of Dab2 and Arh proteins in the compound mutant mice (Fig. 2B, C).”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
The endothelial cholesterol derived from LDL uptake likely is exchangeable with the hepatic pool of cholesterol that is capable in the feedback regulation of its de novo synthesis.
“Therefore, the endothelial cholesterol derived from LDL uptake likely is exchangeable with the hepatic pool of cholesterol that is capable in the feedback regulation of its de novo synthesis.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
The dosage of LDLR adaptor protein is not a limiting factor for LDL uptake.
“The observation suggests that the dosage of LDLR adaptor protein is not a limiting factor for LDL uptake, and the presence of either Dab2 or Arh is sufficient, yet the presence of both adaptors is not additive in the same cell.”
Quote in the paperSubstantial claim - Interpretationnone given§ DISCUSSION
The cholesterol derived from Dab2-mediated LDL uptake in sinusoid endothelial cells resides in a cellular pool that is able to regulate cholesterol synthesis in hepatocytes.
“In the liver, Dab2 participates in LDLR-mediated LDL uptake only through the sinusoid endothelial cells, and the derived cholesterol resides in a cellular pool that is able to regulate cholesterol synthesis in hepatocytes.”
Quote in the paperNot a substantial claim - Premisecitation§ Abstract
Mutations in LDLR that eliminate production of the protein or render the receptor unable to undergo endocytosis attest that LDLR is pivotal in the uptake and removal of LDL from the circulation by both hepatic and peripheral tissues.
“Identification of mutations in LDLR that eliminate the production of the protein or render the receptor unable to undergo endocytosis attests that the LDLR is pivotal in the uptake and removal of LDL from the circulation by both hepatic and peripheral tissues”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Davis, 1986, The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors, Cell. source
- cites [11] Garcia, 2001, Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein, Science. source
- Interpretationreasoning§ DISCUSSION
In the liver, Dab2 participates in LDLR-mediated LDL uptake only through the sinusoid endothelial cells.
“In the liver, Dab2 participates in LDLR-mediated LDL uptake only through the sinusoid endothelial cells, and the derived cholesterol resides in a cellular pool that is able to regulate cholesterol synthesis in hepatocytes.”
Quote in the paperNot a substantial claim - Interpretationown data§ RESULTS
The majority of LDLR locates within hepatocytes rather than the endothelial cells.
“This is consistent with the notion that the majority of LDLR locates within hepatocytes rather than the endothelial cells.”
- Also stated in: § DISCUSSION · plain
“However, the majority of liver LDLR locates within the hepatocytes, and endothelial cells likely only contribute to a very minor level of receptor-mediated LDL uptake.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Interpretationreasoning§ RESULTS
Dab2 mediates a noncell autonomous activity to regulate hepatic HMGCR activity and cholesterol homeostasis.
“This would suggest that Dab2 mediates a noncell autonomous activity to regulate hepatic HMGCR activity and cholesterol homeostasis.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
The combination of Arh and Dab2 is responsible for the majority of adaptor function in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.
“We conclude that the combination of Arh and Dab2 is responsible for the majority of adaptor function in LDLR endocytosis and LDLR-mediated cholesterol homeostasis”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Dab2 does impact LDL uptake through the liver sinusoidal endothelial cells and cholesterol synthesis despite the presence of Arh.
“Nevertheless, we did observe a significant increase in liver cholesterol content in Dab2 knockout animals, suggesting that Dab2 does impact LDL uptake through the liver sinusoidal endothelial cells and cholesterol synthesis despite the presence of Arh.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
In the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis in hepatocytes.
“Thus, in the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis in hepatocytes”
Quote in the paperSubstantial claim - Interpretationreasoning§ RESULTS
Arh acts as the main endocytic adaptor.
“This is consistent with that liver is the main site for LDLR-mediated clearance of LDL particles, and Arh acts as the main endocytic adaptor.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Endothelial cells likely only contribute to a very minor level of receptor-mediated LDL uptake.
“However, the majority of liver LDLR locates within the hepatocytes, and endothelial cells likely only contribute to a very minor level of receptor-mediated LDL uptake.”
Quote in the paperSubstantial claim - Interpretationreasoning§ RESULTS
Liver is the main site for LDLR-mediated clearance of LDL particles.
“This is consistent with that liver is the main site for LDLR-mediated clearance of LDL particles, and Arh acts as the main endocytic adaptor.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
The LDLR is a key determinant of serum cholesterol homeostasis.
“The LDLR is a key determinant of serum cholesterol homeostasis”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Davis, 1986, The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors, Cell. source
- cites [11] Garcia, 2001, Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein, Science. source
- Interpretationown data§ RESULTS
Dab2 is not expressed in Kupffer cells.
“The staining patterns were clearly dissimilar between Dab2 and F4/80 in the same section, and the two immunofluorescent signals were often seen adjacent but not colocalized (Fig. 6C), suggesting that Dab2 is not expressed in Kupffer cells.”
Quote in the paperSubstantial claim - Premisereasoning§ RESULTS
Cholesterol in these mice was exclusively endogenously produced because the high-sucrose diet lacked exogenous cholesterol.
“Cholesterol in these mice was exclusively endogenously produced because the high-sucrose diet lacked exogenous cholesterol.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ RESULTS
The combination of Dab2 and Arh accounts for the majority of adaptor activity responsible for LDLR endocytosis and LDL uptake by MEFs.
“Thus, the combination of Dab2 and Arh accounts for the majority of adaptor activity responsible for LDLR endocytosis and LDL uptake by MEFs, by presenting individual cells with either Arh and/or Dab2 as the endocytic adaptor for LDLR.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
The combined roles of Arh and Dab2 account for the adaptor function in LDLR endocytosis and cholesterol homeostasis in intact animals.
“A model is proposed that the combined roles of Arh and Dab2 account for the adaptor function in LDLR endocytosis and cholesterol homeostasis in intact animals.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Cholesterol derived from Dab2- and LDLR-mediated uptake of LDL in the sinusoid endothelial cells must be able to suppress hepatic HMGCR.
“Because Arh knockout mice have low hepatic HMGCR protein, cholesterol derived from Dab2- and LDLR-mediated uptake of LDL in the sinusoid endothelial cells must be able to suppress hepatic HMGCR.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Arh is the main LDLR endocytic adaptor for clearance of circulating LDL in both liver and extrahepatic tissues.
“We suggest that Arh is the main LDLR endocytic adaptor for clearance of circulating LDL in both liver and extrahepatic tissues.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Dab2-deficient mice have only minor changes in serum cholesterol level.
“Dab2-deficient mice have only minor changes in serum cholesterol level”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Moore, 2013, Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues, BMC Dev. Biol. source
- Interpretationreasoning§ DISCUSSION
Dab2 is likely more relevant in regulating hepatic cholesterol synthesis through its function in sinusoid endothelia.
“The results from the double-knockout mice suggest that Dab2 plays a partially redundant or supplementary role to Arh in mediating LDLR endocytosis and is likely more relevant in regulating hepatic cholesterol synthesis through its function in sinusoid endothelia.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Dab2 plays a partially redundant or supplementary role to Arh in mediating LDLR endocytosis.
“The results from the double-knockout mice suggest that Dab2 plays a partially redundant or supplementary role to Arh in mediating LDLR endocytosis and is likely more relevant in regulating hepatic cholesterol synthesis through its function in sinusoid endothelia.”
Quote in the paperSubstantial claim - Interpretationreasoning§ RESULTS
The presence of both adaptors is not additive in the same cell.
“The observation suggests that the dosage of LDLR adaptor protein is not a limiting factor for LDL uptake, and the presence of either Dab2 or Arh is sufficient, yet the presence of both adaptors is not additive in the same cell.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
The combined roles of Arh and Dab2 account for the majority of the requirement for LDLR endocytosis and clearance of circulating LDL in intact animals.
“Thus, the combined roles of Arh and Dab2 account for the majority of the requirement for LDLR endocytosis and clearance of circulating LDL in intact animals.”
Quote in the paperSubstantial claim - Interpretationreasoning§ RESULTS
Dab2-mediated LDLR endocytosis in the liver sinusoidal endothelial cells is able to regulate hepatic HMGCR expression and cholesterol synthesis.
“Therefore, we conclude that Dab2-mediated LDLR endocytosis in the liver sinusoidal endothelial cells, which contain only a much lower level of LDLR, is able to regulate hepatic HMGCR expression and cholesterol synthesis.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Genetic analysis of kindreds afflicted with autosomal recessive hypercholesterolemia led to the identification of the LDLR endocytic adaptor protein LDLRAP1/ARH.
“Additional genetic analysis of kindreds afflicted with autosomal recessive hypercholesterolemia (ARH) led to the identification of the LDLR endocytic adaptor protein LDLRAP1/ARH”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Garcia, 2001, Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein, Science. source
- Interpretationown data§ RESULTS
A transcriptional regulatory network between the receptors and endocytic adaptors exists.
“Thus, a transcriptional regulatory network between the receptors and endocytic adaptors exists that warrants future investigation.”
Quote in the paperNot a substantial claim - Interpretationown data§ RESULTS
The presence of either Dab2 or Arh is sufficient for LDL uptake.
“The observation suggests that the dosage of LDLR adaptor protein is not a limiting factor for LDL uptake, and the presence of either Dab2 or Arh is sufficient, yet the presence of both adaptors is not additive in the same cell.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 9
- It may state two separate claims as one. 22
- The quote only partly states this claim. 1
Probably not a substantial claim.
Premisecitation§ AbstractThe involvement of Dab2 in cholesterol metabolism in intact animals is uncertain.
“the involvement of Dab2 in cholesterol metabolism in intact animals is uncertain”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Moore, 2013, Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues, BMC Dev. Biol. source
The Results section, “Role of Dab2 in cholesterol metabolism in vivo,” reports significantly elevated serum cholesterol and LDL in Dab2-deficient mice and concludes that Dab2 has a physiological role in cholesterol metabolism. The Discussion likewise describes increased serum cholesterol and LDL in the mutant mice. The paper therefore presents evidence of involvement in intact animals rather than saying that involvement is uncertain. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ AbstractThe main carriers of atherogenic circulating cholesterol in humans are LDL particles, which are produced mainly by the liver to deliver cholesterol to peripheral tissues.
“The main carriers of atherogenic circulating cholesterol in humans are the LDL particles, which are produced mainly by the liver to deliver cholesterol to peripheral tissues”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] Brown, 1984, How LDL receptors influence cholesterol and atherosclerosis, Sci. Am. source
- cites [7] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
- cites [8] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J. Clin. Invest. source
The study summary (section and page unavailable in our copy) establishes that LDL cholesterol circulates in plasma and that the liver plays a major role in its turnover in mice. It does not establish that LDL is the main carrier of atherogenic cholesterol in humans or that its principal role is delivery to peripheral tissues; in the mice studied, most LDL cholesterol returned directly to the liver. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractThe balance of serum cholesterol level is determined by dietary intake, synthesis, and catabolism.
“The balance of serum cholesterol level is determined by dietary intake, synthesis, and catabolism”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] Brown, 1984, How LDL receptors influence cholesterol and atherosclerosis, Sci. Am. source
- cites [7] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
- cites [8] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J. Clin. Invest. source
The paper’s opening passage (page not available in our copy) examines cholesterol synthesis and LDL-cholesterol degradation in mice, and reports that altered LDL turnover changed plasma LDL-cholesterol levels. It does not establish dietary intake as a determinant or support the broader three-part account of serum cholesterol balance. (LLM, conf=0.82)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Study design and conductcitation§ MATERIALS AND METHODSdab2 (fl/df):Sox2-Cre mice are conditional knockouts that are essentially Dab2 null after birth.
“dab2 (fl/df):Sox2-Cre were conditional knockouts shown to be essentially Dab2 null after birth”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Moore, 2013, Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues, BMC Dev. Biol. source
It may state two separate claims as one.
Findingown data§ RESULTSThe liver tissue was LDLR positive throughout, with a slightly higher intensity along the sinusoidal endothelial edges.
“The liver tissue was LDLR positive throughout, with a slightly higher intensive along the sinusoidal endothelial edges (Fig. 6B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ DISCUSSIONDespite an increased liver cholesterol level in either LDLR-null or Arh/Dab2 double-knockout mice, liver HMGCR expression was greatly induced, to a similar extent in both mutant mice.
“Despite an increased liver cholesterol level in either LDLR-null or Arh/Dab2 double-knockout mice, we observed that liver HMGCR expression was greatly induced, to a similar extent in both mutant mice.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown data§ RESULTSThe increased Arh in MEFs contains a modified form showing an increased apparent molecular mass.
“The increased Arh in MEFs also contains a modified form showing an increased apparent molecular mass (Fig. 2B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ RESULTSLDLR and Arh proteins are abundant in liver.
“The presence of proteins were validated by Western blot of tissues obtained from experimental mice, and the results indicate that LDLR and Arh proteins are indeed abundant in liver, whereas Dab2 is much lower in the liver compared with other tissues analyzed (Fig. 1B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ RESULTSDab2 was heterogeneously expressed in the cell population, and only ∼30% of the MEFs were Dab2 positive.
“We further determined that Dab2 was heterogeneously expressed in the cell population, and only ∼30‥ of the MEFs were Dab2 positive (Fig. 4D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSThe serum triglyceride level in the double-knockout mice increased, but not to the same level as in LDLR knockout mice.
“Interestingly, the serum triglyceride level in the double-knockout mice increased, but not to the same level as in LDLR knockout mice (Fig. 3B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ RESULTSDab2 and Arh double-knockout mice were produced in the expected Mendelian ratio and were grossly normal.
“Remarkably, Dab2 and Arh double-knockout mice were produced in the expected Mendelian ratio and were grossly normal.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ RESULTSElimination of Dab2 or LDLR did not elicit a compensatory increase in Arh protein in liver tissues.
“Elimination of Dab2 or LDLR elicited a compensatory increase in Arh protein in MEFs (Fig. 2B) but not in liver tissues (Fig. 2C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSDab2 is expressed in the sinusoid endothelial cells but not in hepatocytes or Kupffer cells in the liver.
“Thus, we conclude that Dab2 is expressed in the sinusoid endothelial cells but not in hepatocytes or Kupffer cells in the liver.”
- Also stated in: § DISCUSSION · plain
“One unexpected finding is that Dab2 is expressed only in sinusoid endothelial cells but not in hepatocytes or Kupffer cells.”
Quote in the paperSubstantial claim- Also stated in: § DISCUSSION · plain
It may state two separate claims as one.
Interpretationreasoning§ RESULTSThe majority of liver LDLR located within the hepatocytes is inaccessible to Dab2, which associates only with LDLR of the sinusoidal endothelial cells.
“Thus, the majority of liver LDLR located within the hepatocytes is inaccessible to Dab2, which associates only with LDLR of the sinusoidal endothelial cells.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown data§ RESULTSCells positive for either Dab2 and/or Arh are sufficient to support LDLR-mediated uptake of BODIPY-labeled LDL and were fluorescently labeled to a similar extent.
“Thus, cells positive for either Dab2 and/or Arh are sufficient to support LDLR-mediated uptake of BODIPY-labeled LDL and were fluorescently labeled to a similar extent; only the cells negative for both Dab2 and Arh remained unlabeled.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ AbstractThe activity and ability of Dab2 to mediate LDLR endocytosis have been demonstrated in cultured cells.
“The activity and ability of Dab2 to mediate LDLR endocytosis have been demonstrated in cultured cells”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Maurer, 2006, The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH, J. Cell Sci. source
It may state two separate claims as one.
Interpretationown data§ DISCUSSIONThe concerted roles of Arh and Dab2 are responsible for the majority of adaptor function for LDLR endocytosis and LDLR-mediated cholesterol clearance from the circulation, as well as the regulation of cholesterol synthesis through controlling HMGCR expression.
“We conclude that the concerted roles of Arh and Dab2 are responsible for the majority of adaptor function for LDLR endocytosis and LDLR-mediated cholesterol clearance from the circulation, as well as the regulation of cholesterol synthesis through controlling HMGCR expression.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationreasoning§ RESULTSThe increased serum cholesterol would be either because of a reduced uptake or an augmented synthesis/secretion.
“Thus, the increased serum cholesterol would be either because of a reduced uptake or an augmented synthesis/secretion.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given§ MATERIALS AND METHODSThe Institutional Animal Care and Use Committee reviewed and approved all the experimental procedures using laboratory mice described in this study.
“The Institutional Animal Care and Use Committee reviewed and approved all the experimental procedures using laboratory mice described in this study”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationreasoning§ DISCUSSIONBecause Arh knockout greatly affects serum cholesterol but not hepatic HMGCR, Arh-mediated, but not Dab2-mediated, LDLR endocytosis is the main activity in the removal of circulating cholesterol.
“Because Arh knockout greatly affects serum cholesterol but not hepatic HMGCR, Arh-mediated, but not Dab2-mediated, LDLR endocytosis is the main activity in the removal of circulating cholesterol.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown data§ DISCUSSIONHepatic cholesterol synthesis is only activated either in the absence of LDLR or by deletion of both Arh and Dab2.
“Hepatic cholesterol synthesis is only activated either in the absence of LDLR or by deletion of both Arh and Dab2.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationreasoning§ DISCUSSIONIn the absence of Arh, LDLR-mediated LDL uptake in liver presumably occurs only in the sinusoid endothelia supported by Dab2 but not in hepatocytes, and only at a very low level.
“In the absence of Arh, LDLR-mediated LDL uptake in liver presumably occurs only in the sinusoid endothelia supported by Dab2 but not in hepatocytes, and only at a very low level.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ AbstractAutosomal recessive hypercholesterolemia (ARH), an LDLR endocytic adaptor, perturbs LDLR function and thus impacts serum cholesterol levels.
“Human mutation analysis revealed that autosomal recessive hypercholesterolemia (ARH), an LDLR endocytic adaptor, perturbs LDLR function and thus impacts serum cholesterol levels”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Garcia, 2001, Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein, Science. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractHepatic cells play major roles in removing LDL from the circulation.
“hepatic cells also play major roles in removing LDL from the circulation”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [6] Brown, 1984, How LDL receptors influence cholesterol and atherosclerosis, Sci. Am. source
- cites [7] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
- cites [8] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J. Clin. Invest. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ AbstractDab2 is potentially an LDLR-selective endocytic clathrin adaptor.
“Another endocytic clathrin adaptor, Disabled-2 (Dab2), is potentially an LDLR-selective adaptor”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Mishra, 2002, Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor, EMBO J. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown data§ RESULTSThe values obtained from either measurement of LDL uptake (number of BODIPY-positive cells or total BODIPY signal) were similar.
“Interestingly, the values obtained from either measurement were similar.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown data§ DISCUSSIONArh is the main LDLR endocytic adaptor involved in the clearance of circulating LDL in both liver and extrahepatic tissues and in the regulation of HMGCR for cholesterol synthesis.
“Dab2 gene ablation alone in mice has a relatively minor impact on serum cholesterol, and the results suggest that Arh is the main LDLR endocytic adaptor involved in the clearance of circulating LDL in both liver and extrahepatic tissues and in the regulation of HMGCR for cholesterol synthesis.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Premisenone given§ RESULTSThe source of circulatory cholesterol was solely from endogenous synthesis in mice on high-sucrose diet.
“In such a situation, the source of circulatory cholesterol was solely from endogenous synthesis.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given§ MATERIALS AND METHODSWestern blot analysis of the cells was used to confirm the genotype obtained from PCR of the head tissues.
“Western blot analysis of the cells was used to confirm the genotype obtained from PCR of the head tissues”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Premisecitation§ AbstractAutosomal dominant familial hypercholesterolemia caused by inactivating mutations in the LDLR gene exhibits a greater serum LDL level and higher degree of severity of symptoms than found with mutations in the ARH gene.
“The autosomal dominant familiar hypercholesterolemia caused by inactivating mutations in the LDLR gene exhibits a greater serum LDL level and higher degree of severity of the symptoms than found with mutations in ARH gene”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Garcia, 2001, Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein, Science. source
It may state two separate claims as one.
Interpretationreasoning§ DISCUSSIONThe absence of both Dab2 and Arh in liver leads to greatly increased liver cholesterol to the level comparable to those of LDLR knockout, likely as a result of unsuppressed synthesis.
“The absence of both Dab2 and Arh in liver leads to greatly increased liver cholesterol to the level comparable to those of LDLR knockout, likely as a result of unsuppressed synthesis.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
Additional endocytic adaptors other than Arh may support LDLR endocytosis.
“Presumably, additional endocytic adaptors other than Arh may support LDLR endocytosis”
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?
Dab2 null mice show increased serum cholesterol.
“Liver/sinusoidal endothelial cells | Increased serum cholesterol”
From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Tao et al., 2016a
The Results report increased serum cholesterol in mice lacking both Dab2 and Arh, not in Dab2-null mice alone. The Discussion says Dab2 ablation alone has a relatively minor impact on serum cholesterol and reports increased liver cholesterol in those mice; liver cholesterol is not serum cholesterol. No page numbers are available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDab2 does not cooperate but complements Arh in LDL receptor endocytosis in the clearance of serum LDL particles.
“The finding leads to the conclusion that Dab2 does not cooperate but complements Arh in LDL receptor endocytosis in the clearance of serum LDL particles.”
From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Tao et al., 2016a
The Results report that either Dab2 or Arh can support LDLR-mediated LDL uptake in mouse cells and that having both is not additive in the same cell. The Discussion describes Dab2 as supplementary to Arh in intact mice, supporting the idea that their roles complement one another in circulating LDL clearance. But the paper does not establish the broader claim that they do not cooperate in that clearance; it calls their roles concerted. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe combination of Arh and Dab2 is responsible for the majority of adaptor functions in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.
“The study concludes that the combination of Arh and Dab2 is responsible for the majority of adaptor functions in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.”
From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Tao et al., 2016a
Dab2 is not expressed in hepatocytes, but rather in the sinusoidal endothelial cells in liver.
“Nevertheless, a surprising finding is that Dab2 is not expressed in hepatocytes, but rather in the sinusoidal endothelial cells in liver (Tao et al., 2016a).”
From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Tao et al., 2016a
In the absence of Arh, the additional loss of Dab2 greatly augments serum LDL and cholesterol levels to an extent similar to that observed in LDL receptor null mice.
“However, in the absence of Arh, the additional loss of Dab2 greatly augments serum LDL and cholesterol levels to an extent similar to that observed in LDL receptor null mice (Tao et al., 2016a).”
From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Tao et al., 2016a
In the absence of Arh, Dab2 in liver endothelial cells regulates the expression of HMG-CoA reductase and cholesterol synthesis in hepatocytes.
“In the absence of Arh, Dab2 in liver endothelial cells regulates the expression of HMG-CoA reductase and cholesterol synthesis in hepatocytes (Tao et al., 2016a).”
From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Tao et al., 2016a
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Genesis of Epithelial Polarity in Early Mammalian Embryos
Xu, X. X., Smith, E. R., & Salas, P. J. I. (2021) · SCIREA journal of biology. · doi:10.54647/biology18174
Embryonic adipose development and consequences in later life
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Self-citationGenesis of Epithelial Polarity in Early Mammalian Embryos
Xu, X., & Smith, E. R. (2023) · SCIREA journal of biology. · doi:10.54647/biology180331
Self-citation
Metadata
- Authors
- Tao, W., Moore, R., Meng, Y., Smith, E. R., & Xu, X.-X.
- Affiliations
- University of Miami (US)
- Corresponding author
- Xu, Xiang-Xi
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 57
- Issue
- 5
- Pages
- 809-817
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC4847628
- OpenAlex
- W2310662648
- Cited by
- 32
- References
- 32
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 2
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Office of Extramural Research, National Institutes of Health (R01 CA095071, R01 CA79716, R01 CA75389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- ArH+, Dab2, Disabled-2, LDL receptor, hypercholesterolemia, LDL clearance, hepatic cholesterol synthesis, HMG-CoA reductase, sinusoidal endothelial cells, atherosclerosis
- MeSH terms
- Animals, Cells, Cultured, Cholesterol, Endocytosis, Female, Homeostasis, Hypercholesterolemia, Lipoproteins, LDL, Male, Mice, Inbred C57BL, Receptors, LDL, Gene Expression, Mice, Knockout, Adaptor Proteins, Vesicular Transport, Adaptor Proteins, Signal Transducing, Atherosclerosis, Apoptosis Regulatory Proteins, Mice, 129 Strain
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.
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