EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis

The FAT-MASH model reproducibly recapitulates the stages of progression of human MASH that include advanced fibrosis and tumors along with changes in the gut microbiome.

“the FAT-MASH model was used, as this model reproducibly recapitulates the stages of progression of human MASH that include advanced fibrosis and tumors along with changes in the gut microbiome.14,33,34”

• cites [14] Tsuchida, 2018, A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer, J. Hepatol. sourcePartly supported

  The Discussion (page not provided) says the paper’s western-diet/CCl4 mouse model develops advanced fibrosis, cirrhosis and liver cancer, recapitulating stages of human NASH progression. The source does not identify this model as “FAT-MASH” or report changes in the gut microbiome, so those parts of the claim are unsupported by this paper. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [33] Wang, 2023, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis, Sci. Transl. Med. sourceSupported
• cites [34] Carter, 2021, Modeling dysbiosis of human NASH in mice: loss of gut microbiome diversity and overgrowth of Erysipelotrichales, PLoS One sourceSupported

Hepatocytes express the highest levels of EHBP1 among all liver cell types.

“We found that hepatocytes expressed the highest levels of EHBP1 among all the liver cell types and that EHBP1 expression was dramatically reduced in cirrhotic livers compared to healthy ones (Figure S1A).”

EHBP1 loss-of-function increases MASH fibrosis in mice.

“EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively.”

• Also stated in: § EHBP1 silencing in hepatocytes promotes liver fibrosis in MASH · hedged

  “Importantly, we also found that EHBP1 silencing induced liver fibrosis, as indicated by the increases in sirius red staining, fibrotic gene expression, and αSMA+ area compared with the control–treated group (Figures 2D, 2E, and S2D).”

EHBP1 overexpression did not alter liver Ldlr mRNA.

“EHBP1 overexpression resulted in significantly reduced liver total LDLR protein levels and hepatocyte cell-surface LDLR without altering liver Ldlr mRNA (Figures 4F, 4G, and S4C).”

The rs10496099 C allele is associated with a higher prevalence of steatosis ≥2.

“We found that the rs10496099 C allele was associated with a higher prevalence of steatosis ≥2, necroinflammation >0, and fibrosis >1 (Figure 1G).”

EHBP1 silencing increased liver steatosis in FAT-MASH mice.

“we found that EHBP1 silencing increased liver steatosis and inflammation, as indicated by increased lipid droplet area, and increased inflammatory cells and inflammatory genes—Adgre1, Tnfa, and Ccl2, and %F4/80+ area compared with the AAV8-H1-shCon (control)–treated group (Figures 2B, 2C, and S2C).”

EHBP1 silencing reduced secreted PCSK9 in culture media from both primary mouse and human hepatocytes without changing Pcsk9 mRNA.

“EHBP1 silencing reduced secreted PCSK9 in the culture media from both primary mouse and human hepatocytes without changing Pcsk9 mRNA in hepatocytes (Figures 5B, 5C, S5D, and S5E)”

Plasma PCSK9 levels were increased in EHBP1-overexpressed MASH mice.

“plasma PCSK9 levels were decreased in EHBP1-silenced MASH mice and increased in EHBP1-overexpressed MASH mice (Figure 5A).”

In mouse fibrotic MASH livers, processes involved in lipid, steroid, and cholesterol metabolism are significantly downregulated.

“Gene ontology analysis revealed that processes involved in lipid, steroid, and cholesterol metabolism were significantly downregulated, whereas processes involved in immune response, extracellular matrix organization, and apoptosis were upregulated in mouse fibrotic MASH livers (Figure 1F).”

EHBP1 overexpression resulted in significantly reduced hepatocyte cell-surface LDLR.

“EHBP1 overexpression resulted in significantly reduced liver total LDLR protein levels and hepatocyte cell-surface LDLR without altering liver Ldlr mRNA (Figures 4F, 4G, and S4C).”

In EHBP1-silenced MASH mice, upregulated genes are enriched for collagen fibril organization, extracellular matrix organization, and immune system processes.

“genes upregulated in EHBP1-silenced MASH mice were enriched for pathways involved in collagen fibril organization, extracellular matrix organization, and immune system processes, whereas downregulated genes were enriched for the epoxygenase P450 pathway, xenobiotic metabolic process, and lipid metabolic process (Figure 2G).”

EHBP1 overexpression reduced TAZ protein levels in FAT-MASH mice.

“EHBP1 overexpression reduced TAZ protein levels and suppressed Ihh mRNA in FAT-MASH mice (Figures 4O, S4H, and S4I).”

EHBP1 overexpression resulted in significantly reduced liver total LDLR protein levels.

“EHBP1 overexpression resulted in significantly reduced liver total LDLR protein levels and hepatocyte cell-surface LDLR without altering liver Ldlr mRNA (Figures 4F, 4G, and S4C).”

Liver EHBP1 mRNA and protein levels are significantly decreased in all examined mouse MASH models.

“mRNA and protein levels of liver EHBP1 were significantly decreased in all the examined mouse MASH models (Figures 1D, S1C, and S1D).”

Decreased PCSK9 secretion aligned with an increase in PCSK9 in EHBP1-silenced liver and hepatocyte lysates.

“the decreased PCSK9 secretion aligned with an increase in PCSK9 in EHBP1-silenced liver and hepatocyte lysates (Figure S5F).”

Collagen gene expression was induced in EHBP1-silenced MASH livers.

“collagen gene expression was induced in EHBP1-silenced MASH livers (Figure S2E).”

EHBP1 silencing enhanced TAZ protein levels in primary hepatocytes.

“we found that EHBP1 silencing enhanced TAZ protein levels in primary hepatocytes (Figures 4P and S4M).”

EHBP1 silencing induced liver fibrosis in FAT-MASH mice.

“Importantly, we also found that EHBP1 silencing induced liver fibrosis, as indicated by the increases in sirius red staining, fibrotic gene expression, and αSMA+ area compared with the control–treated group (Figures 2D, 2E, and S2D).”

EHBP1 expression is restored during disease regression when MASH mice are switched back to a normal chow diet.

“EHBP1 expression was restored during disease regression when MASH mice were switched back to a normal chow diet (Figure S1G).”

Cholesterol delivered by LDL particles that contain approximately 50% cholesterol markedly increased TAZ in primary hepatocytes.

“cholesterol delivered by LDL particles that contain approximately 50% cholesterol41 markedly increased TAZ in primary hepatocytes (Figure 4M).”

• cites [41] Rajman, 1999, LDL particle size: an important drug target?, Br. J. Clin. Pharmacol. sourceNot checked yet

MICALL1 expression is reduced in both human and mouse MASH livers at the protein and mRNA levels.

“MICALL1 expression was reduced in both human and mouse MASH livers at the protein and mRNA levels, while the expression of EHD1 and Rabenosyn5 was not altered in MASH”

After adjustment for sex, age, BMI, and the PNPLA3 G allele, the rs10496099 C allele is associated with a higher risk of steatosis ≥2.

“a multivariate nominal regression analysis adjusted for sex, age, BMI (body mass index), and the PNPLA3 G allele (the main genetic predictor of MASLD) revealed that the rs10496099 C allele was associated with a higher risk of steatosis ≥2, necroinflammation >0, and fibrosis >1 (Table S3).”

EHBP1 silencing increased liver inflammation in FAT-MASH mice.

“we found that EHBP1 silencing increased liver steatosis and inflammation, as indicated by increased lipid droplet area, and increased inflammatory cells and inflammatory genes—Adgre1, Tnfa, and Ccl2, and %F4/80+ area compared with the AAV8-H1-shCon (control)–treated group (Figures 2B, 2C, and S2C).”

Hepatocyte EHBP1-silenced MASH livers had increased Ihh mRNA.

“hepatocyte EHBP1–silenced MASH livers had increased TAZ at the protein level (Figure 4N) and increased Ihh mRNA (Figure S4F).”

EHBP1 overexpression decreased liver steatosis in FAT-MASH mice.

“EHBP1 overexpression in hepatocytes decreased liver steatosis and inflammation, as indicated by decreased lipid droplet area, and decreased inflammatory cells and inflammatory genes (Figures 3B, 3C, and S3B).”

In mouse fibrotic MASH livers, processes involved in immune response, extracellular matrix organization, and apoptosis are upregulated.

“Gene ontology analysis revealed that processes involved in lipid, steroid, and cholesterol metabolism were significantly downregulated, whereas processes involved in immune response, extracellular matrix organization, and apoptosis were upregulated in mouse fibrotic MASH livers (Figure 1F).”

Ldlr mRNA was not altered in livers from shEhbp1-treated FAT-MASH mice.

“while Ldlr mRNA was not altered in livers from shEhbp1-treated FAT-MASH mice, LDLR protein levels were significantly increased (Figures 4A and S4A).”

The rs10496099 C allele is associated with a higher prevalence of necroinflammation >0.

“We found that the rs10496099 C allele was associated with a higher prevalence of steatosis ≥2, necroinflammation >0, and fibrosis >1 (Figure 1G).”

EHBP1 overexpression suppressed Ihh mRNA in FAT-MASH mice.

“EHBP1 overexpression reduced TAZ protein levels and suppressed Ihh mRNA in FAT-MASH mice (Figures 4O, S4H, and S4I).”

EHBP1 did not alter the capacity of PCSK9 for LDLR degradation.

“EHBP1 did not alter the capacity of PCSK9 for LDLR degradation (Figure S5B), indicating that EHBP1 does not affect PCSK9-induced LDLR internalization and subsequent degradation.”

EHBP1 overexpression reduced liver fibrosis in FAT-MASH mice.

“EHBP1 overexpression also reduced liver fibrosis, as indicated by the decreases in sirius red staining, fibrotic gene expression, and the αSMA+ area in AAV8-TBGS1-Ehbp1-treated MASH mice, as well as plasma ALT and AST (Figures 3D–3F and S3C).”

Increased cell-surface LDLR was associated with elevated liver total cholesterol in EHBP1-silenced MASH mice.

“increased cell-surface LDLR was associated with elevated liver total cholesterol in EHBP1-silenced MASH mice (Figure 4C).”

Sortilin was decreased in EHBP1-deficient primary mouse and human hepatocytes.

“we found that sortilin was decreased in EHBP1-deficient primary mouse and human hepatocytes (Figure 5D).”

EHBP1 gain-of-function decreases MASH fibrosis in mice.

“EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively.”

• Also stated in: § EHBP1 overexpression in hepatocytes eliminates liver fibrosis in MASH · hedged

  “EHBP1 overexpression also reduced liver fibrosis, as indicated by the decreases in sirius red staining, fibrotic gene expression, and the αSMA+ area in AAV8-TBGS1-Ehbp1-treated MASH mice, as well as plasma ALT and AST (Figures 3D–3F and S3C).”

EHBP1 silencing enhanced liver triglyceride levels in MASH mice.

“EHBP1 silencing enhanced liver triglyceride (TG) levels in MASH mice (Figure S4B), consistent with increased steatosis.”

The rs10496099 C allele is associated with a higher prevalence of fibrosis >1.

“We found that the rs10496099 C allele was associated with a higher prevalence of steatosis ≥2, necroinflammation >0, and fibrosis >1 (Figure 1G).”

EHBP1 mRNA levels are reduced in human liver biopsies from patients carrying the rs10496099 C allele.

“we evaluated EHBP1 expression in human liver biopsies from which RNA-seq data were available36 (Table S4) and observed reduced mRNA levels in patients carrying the C allele (Figure 1H)”

• cites [36] Meroni, 2022, Low lipoprotein(a) levels predict hepatic fibrosis in patients with nonalcoholic fatty liver disease, Hepatol. Commun. sourceNot checked yet

Stabilizing retromer is effective in mitigating MASH fibrosis.

“Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis.”

Plasma ALT and AST levels were enhanced in shEhbp1-treated MASH mice.

“plasma ALT and AST levels were enhanced in shEhbp1-treated MASH mice (Figure 2F), indicating that liver injury was elevated in hepatocyte EHBP1–silenced MASH mice.”

Human fibrotic MASH livers have decreased EHBP1.

“We show that human fibrotic MASH livers have decreased EHBP1, a GWAS locus associated with LDL cholesterol”

• Also stated in: § RESULTS · plain

  “compared to the control group, hepatocyte EHBP1 was markedly reduced in MASH livers (Figure 1A).”

• Also stated in: § RESULTS · plain

  “EHBP1 expression was decreased in both human and nonhuman primate17,18 fibrotic MASH livers (Figures 1B, 1C, and S1B).”

EHBP1 deficiency affects the intracellular localization of retromer.

“At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization.”

• Also stated in: § EHBP1 promotes sortilin-mediated PCSK9 secretion · plain

  “EHBP1 silencing resulted in redistribution of Vps26a retromer from peripheral to perinuclear regions (Figure 5N).”

EHBP1 expression is dramatically reduced in cirrhotic livers compared to healthy livers.

“EHBP1 expression was dramatically reduced in cirrhotic livers compared to healthy ones (Figure S1A).”

Hepatocyte EHBP1-silenced MASH livers had increased TAZ at the protein level.

“hepatocyte EHBP1–silenced MASH livers had increased TAZ at the protein level (Figure 4N) and increased Ihh mRNA (Figure S4F).”

After adjustment for sex, age, BMI, and the PNPLA3 G allele, the rs10496099 C allele is associated with a higher risk of necroinflammation >0.

“a multivariate nominal regression analysis adjusted for sex, age, BMI (body mass index), and the PNPLA3 G allele (the main genetic predictor of MASLD) revealed that the rs10496099 C allele was associated with a higher risk of steatosis ≥2, necroinflammation >0, and fibrosis >1 (Table S3).”

The uptake of LDL was enhanced in EHBP1-silenced hepatocytes.

“the uptake of LDL was enhanced in EHBP1-silenced hepatocytes (Figure 4L).”

LDLR protein levels were significantly increased in livers from shEhbp1-treated FAT-MASH mice.

“while Ldlr mRNA was not altered in livers from shEhbp1-treated FAT-MASH mice, LDLR protein levels were significantly increased (Figures 4A and S4A).”

EHBP1 overexpression decreased liver inflammation in FAT-MASH mice.

“EHBP1 overexpression in hepatocytes decreased liver steatosis and inflammation, as indicated by decreased lipid droplet area, and decreased inflammatory cells and inflammatory genes (Figures 3B, 3C, and S3B).”

Plasma PCSK9 levels were decreased in EHBP1-silenced MASH mice.

“plasma PCSK9 levels were decreased in EHBP1-silenced MASH mice and increased in EHBP1-overexpressed MASH mice (Figure 5A).”

EHBP1 silencing increased cell-surface LDLR in hepatocytes.

“we found that EHBP1 silencing increased cell-surface LDLR in hepatocytes (Figure 4B).”

In EHBP1-silenced MASH mice, downregulated genes are enriched for the epoxygenase P450 pathway, xenobiotic metabolic process, and lipid metabolic process.

“genes upregulated in EHBP1-silenced MASH mice were enriched for pathways involved in collagen fibril organization, extracellular matrix organization, and immune system processes, whereas downregulated genes were enriched for the epoxygenase P450 pathway, xenobiotic metabolic process, and lipid metabolic process (Figure 2G).”

Pcsk9 mRNA was not altered in either EHBP1-silenced or EHBP1-overexpressed MASH livers.

“Pcsk9 mRNA was not altered in either EHBP1-silenced or EHBP1-overexpressed MASH livers (Figure S5C)”

The GAN diet yielded mild fibrosis even after 26 weeks of feeding compared with the profound fibrosis in the 10-week FAT-MASH model.

“although the GAN diet yielded mild fibrosis even after 26 weeks of feeding compared with the profound fibrosis in the 10-week FAT-MASH model (Figure 2D vs. 2K).”

EHBP1-silenced MASH mice had increased free cholesterol in the liver.

“EHBP1-silenced MASH mice had increased free cholesterol in the liver (Figure 4D), which was confirmed by the enhanced Filipin staining, a probe for free cholesterol22 (Figure 4E).”

After adjustment for sex, age, BMI, and the PNPLA3 G allele, the rs10496099 C allele is associated with a higher risk of fibrosis >1.

“a multivariate nominal regression analysis adjusted for sex, age, BMI (body mass index), and the PNPLA3 G allele (the main genetic predictor of MASLD) revealed that the rs10496099 C allele was associated with a higher risk of steatosis ≥2, necroinflammation >0, and fibrosis >1 (Table S3).”

TPT-260 treatment significantly reduced plasma ALT and AST.

“TPT-260 treatment significantly reduced plasma ALT and AST (Figure 6A, right panel), suggesting a protective role of the retromer complex in MASH.”

TPT-260 treatment enhanced retromer components Vps26a and Vps35 in MASH livers.

“TPT-260 treatment enhanced retromer components Vps26a and Vps35 in MASH livers (Figure S6E).”

In the FAT-MASH model, compensatory pathways seem not to be efficient in EHBP1-silenced MASH mice.

“However, in the FAT-MASH model, those compensatory pathways seem not to be efficient in EHBP1-silenced MASH mice.”

MASH-relevant inflammatory cytokine TNFα suppresses EHBP1 expression.

“We now show that MASH-relevant inflammatory cytokine TNFα suppresses EHBP1 expression and increases TAZ.”

EHBP1 decreases LDLR and cholesterol uptake in hepatocytes.

“Our mechanistic studies demonstrate that EHBP1 facilitates sortilin-mediated PCSK9 secretion and decreases LDLR and cholesterol uptake in hepatocytes, leading to the suppression of hepatocyte TAZ and to MASH fibrosis (Figure S7G).”

The loss-of-function EHBP1 rs10496099 T>C genetic variation in MASLD patients is associated with more liver fibrosis.

“The loss-of-function EHBP1 rs10496099 T>C genetic variation in MASLD patients is associated with more liver fibrosis.”

• AssumptionRests on an assumption: The EHBP1 rs10496099 T>C genetic variation is loss-of-function.

PPARα modulates EHBP1 expression in primary hepatocytes.

“Lastly, our study shows that TNFα and PPARα modulate EHBP1 expression in primary hepatocytes, but whether they alter EHBP1-mediated cholesterol homeostasis in vivo is still unknown.”

EHBP1-overexpressed MASH mice have decreased liver fibrosis.

“EHBP1-silenced and EHBP1-overexpressed MASH mice have increased and decreased liver fibrosis, respectively.”

Decreased TAZ was found in TPT-260-treated MASH livers.

“decreased TAZ was also found in TPT-260-treated MASH livers (Figure 6K).”

TNFα expression was induced in both human and mouse MASH livers, including FAT-MASH, FPC, and CDAHFD livers.

“TNFα expression was induced in both human and mouse MASH livers, including FAT-MASH, FPC, and CDAHFD livers (Figures 7B and 7C)”

• AssumptionRests on an assumption: Increased inflammation is a hallmark of MASH and plays a pivotal role in MASH progression through upregulating key molecules associated with lipid metabolism and fibrosis in the liver.

EHBP1 interacted with sortilin and retromer units Vps35 and Vps26a in isolated primary mouse hepatocytes and AML12 cells.

“EHBP1 interacted with sortilin and retromer units—Vps35 and Vps26a in isolated primary mouse hepatocytes and AML12 cells (Figures 5H and S5K).”

Increased LDLR was associated with an increase of LDL uptake.

“The increased LDLR was associated with an increase of LDL uptake (Figure 5M)”

Reduced EHBP1 was confirmed in primary hepatocytes isolated from mice with hepatocyte-specific deletion of Ppara (PparaHKO) compared to Pparafl/fl.

“The reduced EHBP1 was also confirmed in primary hepatocytes isolated from mice with hepatocyte-specific deletion of Ppara (PparaHKO) compared to Pparafl/fl (Figure S7B).”

EHBP1 facilitates sortilin-mediated PCSK9 secretion in hepatocytes.

“Our mechanistic studies demonstrate that EHBP1 facilitates sortilin-mediated PCSK9 secretion and decreases LDLR and cholesterol uptake in hepatocytes, leading to the suppression of hepatocyte TAZ and to MASH fibrosis (Figure S7G).”

Ppara silencing using siRNA decreased EHBP1 expression in primary hepatocytes.

“when Ppara was silenced using siRNA, PPARα deficiency decreased EHBP1 expression in primary hepatocytes (Figure 7F).”

EHD1 expression is not altered in MASH livers.

“In line with this concept, EHD1 expression is not altered in MASH livers.”

Deficiency of the retromer complex dramatically reduced sortilin in primary hepatocytes and AML12 cells.

“the deficiency of the retromer complex dramatically reduced sortilin in primary hepatocytes and AML12 cells (Figures 5J and S5N).”

EHBP1 silencing accelerated sortilin degradation.

“the cycloheximide (CHX) chase assay showed that EHBP1 silencing accelerated sortilin degradation (Figure 5G)”

TPT-260 did not increase EHBP1.

“TPT-260 did not increase EHBP1, consistent with an upper stream role of EHBP1 in regulating retromer.”

PPARα is one of the top candidates for transcription factors that control EHBP1.

“We searched the PathwayNet database for potential transcription factors that control EHBP1 and found that PPARα is one of the top candidates.”

EHBP1 silencing resulted in redistribution of Vps26a retromer from peripheral to perinuclear regions.

“EHBP1 silencing resulted in redistribution of Vps26a retromer from peripheral to perinuclear regions (Figure 5N).”

Liver Vps26a protein but not mRNA levels were reduced in the FAT-MASH model.

“liver Vps26a protein but not mRNA levels were reduced in the FAT-MASH model (Figures S6A and S6B)”

EHBP1-silenced MASH mice have increased liver fibrosis.

“EHBP1-silenced and EHBP1-overexpressed MASH mice have increased and decreased liver fibrosis, respectively.”

PPARα silencing in primary mouse hepatocytes led to reduced sortilin and increased LDLR and TAZ.

“PPARα silencing in primary mouse hepatocytes also led to reduced sortilin and increased LDLR and TAZ (Figure 7H).”

Sort1 mRNA levels were not significantly changed in either EHBP1-silenced or EHBP1-overexpressed MASH livers.

“Sort1 mRNA levels were not significantly changed in either EHBP1-silenced or EHBP1-overexpressed MASH livers (Figure S5J)”

EHBP1 interacts with retromer in an EHD1-independent manner in hepatocytes.

“Our finding that EHBP1 interacts with retromer in an EHD1-independent manner in hepatocytes is intriguing, as this indicates that EHBP1 may regulate sortilin-mediated PCSK9 secretion and MASH independent of EHD proteins.”

EHBP1 stabilizes sortilin potentially via affecting the intracellular location of retromer.

“Moreover, at the cellular level, we show that EHBP1 stabilizes sortilin potentially via affecting the intracellular location of retromer.”

EHBP1 partially co-localized with sortilin and Vps35 retromer in hepatocytes.

“Confocal microscopy confirmed that EHBP1 partially co-localized with sortilin and Vps35 retromer in hepatocytes (Figures 5I and S5M).”

The interaction of EHBP1 with retromer did not require EHD1.

“the interaction of EHBP1 with retromer did not require EHD1 (Figure S5L).”

TNFα modulates EHBP1 expression in primary hepatocytes.

“Lastly, our study shows that TNFα and PPARα modulate EHBP1 expression in primary hepatocytes, but whether they alter EHBP1-mediated cholesterol homeostasis in vivo is still unknown.”

MASH-relevant inflammatory cytokine TNFα increases TAZ.

“We now show that MASH-relevant inflammatory cytokine TNFα suppresses EHBP1 expression and increases TAZ.”

Retromer is required for sortilin stabilization.

“a protein complex required for sortilin stabilization.”

• Also stated in: § EHBP1 promotes sortilin-mediated PCSK9 secretion · plain

  “Retromer-mediated retrograde transport of sortilin can stabilize sortilin through escaping from its lysosomal degradation.50–52”

• cites [50] Mari, 2008, SNX1 defines an early endosomal recycling exit for sortilin and mannose 6-phosphate receptors, Traffic sourceNot checked yet
• cites [51] Pan, 2017, Sortilin and retromer mediate retrograde transport of Glut4 in 3T3-L1 adipocytes, Mol. Biol. Cell sourceNot checked yet
• cites [52] Johannes, 2008, Tracing the retrograde route in protein trafficking, Cell sourceNot checked yet

EHBP1 reduces TAZ, a fibrogenic effector.

“leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector.”

The EHBP1 rs10496099 T>C variant is loss-of-function.

“indicating that the EHBP1 rs10496099 T>C variant is loss-of-function.”

Hepatocyte EHBP1 plays a protective role against MASH.

“our in vivo EHBP1 loss- and gain-of-function studies demonstrate that hepatocyte EHBP1 plays a protective role against MASH.”

EHBP1 promotes PCSK9 secretion.

“which suggests that EHBP1 promotes PCSK9 secretion.”

EHBP1 decreases LDL uptake.

“leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector.”

EHBP1 promotes PCSK9 secretion by enhancing sortilin.

“These results suggest that EHBP1 promotes PCSK9 secretion by enhancing sortilin.”

EHBP1 promotes sortilin-mediated PCSK9 secretion.

“Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector.”

• Also stated in: § EHBP1 promotes sortilin-mediated PCSK9 secretion · hedged

  “These results suggest that EHBP1 promotes PCSK9 secretion by enhancing sortilin.”

EHBP1 may play a protective role against MASH progression.

“These human studies on the EHBP1 SNP rs10496099 T>C variant indicate that EHBP1 may play a protective role against MASH progression.”

EHBP1-induced plasma PCSK9 is regulated via enhancing PCSK9 secretion but not Pcsk9 expression.

“EHBP1-induced plasma PCSK9 is regulated via enhancing PCSK9 secretion but not Pcsk9 expression.”

EHBP1 promotes LDLR degradation.

“leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector.”

The TNFα/PPARα pathway suppresses EHBP1 in MASH.

“Moreover, we show that the TNFα/PPARα pathway suppresses EHBP1 in MASH.”

• Also stated in: § TNFα suppresses EHBP1 expression in hepatocytes · hedged

  “Together, these data indicate that TNFα suppresses EHBP1 expression by suppressing PPARα in hepatocytes”

TNFα suppresses EHBP1 expression by suppressing PPARα in hepatocytes during MASH progression.

“Together, these data indicate that TNFα suppresses EHBP1 expression by suppressing PPARα in hepatocytes during MASH progression.”

The data reveal a previously undescribed hepatic cholesterol metabolism pathway by dissecting the interplay of the four cholesterol-associated GWAS loci and their links to the retromer complex in MASH.

“In summary, the data in this report have revealed a previously undescribed hepatic cholesterol metabolism pathway by dissecting the interplay of the four cholesterol-associated GWAS loci and their links to the retromer complex in the context of MASH.”

EHBP1-suppressed inflammation is likely due to decreased hepatic cholesterol content.

“it is likely that EHBP1-suppressed inflammation is simply due to the decreased hepatic cholesterol content.”

The protective effect of EHBP1 is abolished by TNFα-mediated suppression of EHBP1 expression during MASH.

“However, the protective effect of EHBP1 is abolished by the TNFα-mediated suppression of EHBP1 expression during MASH.”

PPARα may serve as a transcription factor for EHBP1.

“indicating that PPARα may serve as a transcription factor for EHBP1.”

Cholesterol accumulation can induce inflammation.

“since cholesterol accumulation can induce inflammation,79,80”

• cites [79] Mueller, 2021, Cholesterol accumulation as a driver of hepatic inflammation under translational dietary conditions can be attenuated by a multicomponent Medicine, Front. Endocrinol. (Lausanne) sourceNot checked yet
• cites [80] Tall, 2015, Cholesterol, inflammation and innate immunity, Nat. Rev. Immunol. sourceNot checked yet

Most in vivo experiments were conducted in the FAT-MASH model.

“Most in vivo experiments were conducted in the FAT-MASH model, and thus further work is needed to show the importance of EHBP1 in human MASH.”

Stabilizing the retromer complex may be a novel therapeutic approach to treat MASH.

“These data suggest that stabilizing the retromer complex may be a novel therapeutic approach to treat MASH.”

Suppressed EHBP1 during MASH may result from increased TNFα.

“our data suggest that suppressed EHBP1 during MASH may result from increased TNFα.”

• AssumptionRests on an assumption: Increased inflammation is a hallmark of MASH and plays a pivotal role in MASH progression through upregulating key molecules associated with lipid metabolism and fibrosis in the liver.

Other randomized trials with statins showed no significant improvement in liver histological features of MASH patients.

“although other randomized trials with statins showed no significant improvement in liver histological features of MASH patients94”

• cites [94] Nelson, 2009, A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial, J. Clin. Gastroenterol. sourceNot checked yet

The key causative experiment was confirmed using the GAN MASH model.

“Nonetheless, the key causative experiment was confirmed using the GAN MASH model, which was recently ranked as having the highest proximity to human MASLD among the commonly used murine MASH diets.”

• AssumptionRests on an assumption: The GAN MASH model has the highest proximity to human MASLD among the commonly used murine MASH diets.

Retromer deficiency may enhance TAZ via increasing the uptake of LDL cholesterol.

“indicating that retromer deficiency may enhance TAZ via increasing the uptake of LDL cholesterol.”

Inflammatory signaling can disrupt cholesterol homeostasis and exacerbate cholesterol accumulation.

“On the other hand, inflammatory signaling can disrupt cholesterol homeostasis and exacerbate cholesterol accumulation.60,81”

• cites [60] Field, 2010, TNF-alpha decreases ABCA1 expression and attenuates HDL cholesterol efflux in the human intestinal cell line Caco-2, J. Lipid Res. sourceNot checked yet
• cites [81] Zhao, 2011, Inflammatory stress exacerbates hepatic cholesterol accumulation via increasing cholesterol uptake and de novo synthesis, J. Gastroenterol. Hepatol. sourceNot checked yet

Retromer stabilization is a novel therapeutic strategy for MASH.

“Thus, our study highlights retromer stabilization as a novel therapeutic strategy for MASH.”

EHBP1 promotes sortilin stability.

“indicating that EHBP1 promotes sortilin stability.”

Inflammation can amplify cholesterol dysregulation, such as via abolishing EHBP1-mediated cholesterol homeostasis.

“Therefore, our study provides evidence that inflammation can amplify cholesterol dysregulation, such as via abolishing EHBP1-mediated cholesterol homeostasis.”

Retromer becomes unstable during MASH progression.

“indicating that retromer becomes unstable during MASH progression.”

TNFα suppresses EHBP1 expression by suppressing PPARα in hepatocytes.

“Together, these data indicate that TNFα suppresses EHBP1 expression by suppressing PPARα in hepatocytes”

• AssumptionRests on an assumption: Increased inflammation is a hallmark of MASH and plays a pivotal role in MASH progression through upregulating key molecules associated with lipid metabolism and fibrosis in the liver.

Excessive cholesterol can directly induce inflammatory pathways.

“On the one hand, excessive cholesterol can directly induce inflammatory pathways.80”

• cites [80] Tall, 2015, Cholesterol, inflammation and innate immunity, Nat. Rev. Immunol. sourceNot checked yet

EHBP1 promotes sortilin-mediated PCSK9 secretion potentially via modulating retromer.

“These data suggest that EHBP1 promotes sortilin-mediated PCSK9 secretion potentially via modulating retromer.”

There is a positive feedback loop between cholesterol accumulation and inflammation.

“Our investigation into why EHBP1 expression is reduced in MASH livers led to the discovery of a positive feedback loop between cholesterol accumulation and inflammation.”

Hepatocyte TAZ has a pro-inflammatory role in MASH.

“since we previously showed that hepatocyte TAZ has a pro-inflammatory role in MASH.15”

• cites [15] Wang, 2016, Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis, Cell Metab. sourceNot checked yet