β‐Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis

Thompson, Michael D.; Moghe, Akshata; Cornuet, Pamela; Marino, Rebecca; Tian, Jianmin; Wang, Pengcheng; Ma, Xiaochao; Abrams, Marc; Locker, Joseph; Monga, Satdarshan P.; Nejak‐Bowen, Kari

doi:10.1002/hep.29371

Cited by 54 publications

(89 citation statements)

References 41 publications

(46 reference statements)

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“…SHP, which is activated by FXR and suppresses BA synthesis through repression of Cyp7a1 expression, is unchanged in DKO mice before and after BDL. However, Cyp7a1, which catalyzes the rate‐limiting step in the classical BA biosynthesis pathway, is decreased in DKO mice at baseline, similar to β‐catenin KO mice, and is nonsignificantly decreased after BDL (Fig. A).…”

Section: Resultssupporting

confidence: 92%

“…The decreased accumulation of BAs occurs because of enhanced FXR activation, which is negatively regulated by β‐catenin through direct binding. Lack of β‐catenin eliminates sequestration and corepression of FXR, resulting in decreased BA synthesis and increased elimination . The pool of β‐catenin‐bound FXR is responsive to BA stimulation, which causes transient dissociation of the complex and nuclear localization of FXR.…”

supporting

confidence: 83%

“…In these studies, we sought to expand on previous findings that absence of β‐catenin protein and not its transcriptional activity regulates FXR during cholestasis. In our previous publication, we showed that β‐catenin small interfering RNA increased SHP activity secondary to a decreased FXR/β‐catenin association, while treatment with ICG‐001, a small molecule that antagonizes β‐catenin/TCF4 transcriptional activity without reducing protein levels of β‐catenin, does not induce SHP. To determine the relevance of these findings in the development and progression of cholestasis in vivo , we used LRP5/6 KO (DKO) mice, which have disrupted canonical Wnt signaling but intact β‐catenin .…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that conditional knockout (KO) mice lacking β‐catenin in liver exhibited modestly higher basal hepatic BA than wild‐type (WT) mice; this was likely due to dilated biliary canaliculi and loss of tight junction proteins . Despite this, loss of β‐catenin results in maintenance of homeostatic BA levels after BDL in contrast to WT mice, which have significantly higher BA levels . Thus, β‐catenin KO mice are protected from BA‐induced cholestatic injury, resulting in fewer bile infarcts, less ductular response and fibrosis, and increased overall survival.…”

mentioning

confidence: 99%

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Activation of WNT/Beta‐Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta‐Catenin Complex After Murine Bile Duct Ligation

Zhang¹,

Nakao²,

Luo³

et al. 2019

Hepatol Commun

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We have recently shown that loss of β‐catenin prevents the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL) due to loss of the inhibitory farnesoid X receptor (FXR)/β‐catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/β‐catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but β‐catenin is intact (low‐density lipoprotein receptor‐related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte β‐catenin expression (serine 45 mutated to aspartic acid [S45D] transgenic [TG] mice). Despite decreased biliary injury after BDL, hepatic injury, fibrosis, and inflammation were comparable in DKO and wild‐type (WT) mice. Notably, the FXR/β‐catenin complex was maintained in DKO livers after BDL, coincident with significantly elevated hepatic BA levels. Similarly, TG mice did not display accelerated injury or increased mortality despite overexpression of β‐catenin. There was no augmentation of FXR/β‐catenin association in TG livers; this resulted in equivalent hepatic BAs in WT and TG mice after BDL. Finally, we analyzed the effect of BDL on β‐catenin activity and identified an increase in periportal cytoplasmic stabilization and association with T‐cell factor 4 that correlated with increased expression of distinct downstream target genes. Conclusion: Localization of β‐catenin and expression of Wnt‐regulated genes were altered in liver after BDL; however, neither elimination of Wnt/β‐catenin signaling nor overexpression of β‐catenin in hepatocytes significantly impacted the phenotype or progression of BA‐driven cholestatic injury.

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Section: Resultssupporting

confidence: 92%

supporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of WNT/Beta‐Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta‐Catenin Complex After Murine Bile Duct Ligation

Zhang¹,

Nakao²,

Luo³

et al. 2019

Hepatol Commun

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“…An important pathogenic component of cholestatic liver disease involves toxic bile exposure to hepatocytes 4, 5. Injury to biliary epithelium results in local inflammation, loss of cholangiocyte tight junctions, and extravasation of bile salts, which induce local hepatocyte death and periductular fibrosis.…”

mentioning

confidence: 99%

Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

Erstad

Farrar

Ghoshal

et al. 2018

Hepatology Communications

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We examined a novel farnesoid X receptor agonist, EDP‐305, for its antifibrotic effect in bile duct ligation (BDL) and choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) models of hepatic injury. We used molecular magnetic resonance imaging with the type 1 collagen‐binding probe EP‐3533 and the oxidized collagen‐specific probe gadolinium hydrazide to noninvasively measure treatment response. BDL rats (n = 8 for each group) were treated with either low or high doses of EDP‐305 starting on day 4 after BDL and were imaged on day 18. CDAHFD mice (n = 8 for each group) were treated starting at 6 weeks after the diet and were imaged at 12 weeks. Liver tissue was subjected to pathologic and morphometric scoring of fibrosis, hydroxyproline quantitation, and determination of fibrogenic messenger RNA expression. High‐dose EDP‐305 (30 mg/kg) reduced liver fibrosis in both the BDL and CDAHFD models as measured by collagen proportional area, hydroxyproline analysis, and fibrogenic gene expression (all P < 0.05). Magnetic resonance signal intensity with both EP‐3533 in the BDL model and gadolinium hydrazide in the CDAHFD model was reduced with EDP‐305 30 mg/kg treatment (P < 0.01). Histologically, EDP‐305 30 mg/kg halted fibrosis progression in the CDAHFD model. Conclusion: EDP‐305 reduced fibrosis progression in rat BDL and mouse CDAHFD models. Molecular imaging of collagen and oxidized collagen is sensitive to changes in fibrosis and could be used to noninvasively measure treatment response in clinical trials. (Hepatology Communications 2018;2:821‐835)

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β‐Catenin Signaling

Monga

2020

The Liver

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β‐Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis

Abstract: We have identified an FXR/β-catenin interaction whose modulation through β-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955-971).

Cited by 54 publications

References 41 publications

Activation of WNT/Beta‐Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta‐Catenin Complex After Murine Bile Duct Ligation

Activation of WNT/Beta‐Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta‐Catenin Complex After Murine Bile Duct Ligation

Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

β‐Catenin Signaling

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