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?-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis.

ABSTRACT: Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/?-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific ?-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for ?-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that ?-catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of ?-catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of ?-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of ?-catenin expression during cholestatic injury reduces ?-catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. CONCLUSION:We have identified an FXR/?-catenin interaction whose modulation through ?-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955-971).

SUBMITTER: Thompson MD

PROVIDER: S-EPMC5771988 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Thompson Michael D MD Moghe Akshata A Cornuet Pamela P Marino Rebecca R Tian Jianmin J Wang Pengcheng P Ma Xiaochao X Abrams Marc M Locker Joseph J Monga Satdarshan P SP Nejak-Bowen Kari K

Hepatology (Baltimore, Md.) 20180126 3

Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/β-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific β-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice ex ...[more]

PMID: 28714273

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Project description:Cholestasis, characterized by disturbance of bile formation, is a common pathological condition that can induce several serious liver diseases. As a kind of trigger, estrogen-induced cholestasis belongs to drug-induced cholestasis. Paeoniflorin is the most abundant bioactive constituent in Paeonia lactiflora Pall., Paeonia suffruticosa Andr., or Paeonia veitchii Lynch, a widely used herbal medicine for treating hepatic disease over centuries in China. However, the pharmacologic effect and mechanism of paeoniflorin on estrogen-induced cholestasis remain unclear. In this experiment, the pharmacological effect of paeoniflorin on EE-induced cholestasis in rats was evaluated comprehensively for the first time. Ultra-high-performance liquid chromatography coupled with Q-Exactive orbitrap mass spectrometer was used to monitor the variation of bile acid levels and composition. It was demonstrated that paeoniflorin alleviated 17α-ethinylestradiol (EE)-induced cholestasis dose-dependently, characterized by a decrease of serum biochemical indexes, recovery of bile flow, amelioration of hepatic and ileal histopathology, and reduction of oxidative stress. In addition, paeoniflorin intervention restored EE-disrupted bile acid homeostasis in enterohepatic circulation. Further mechanism studies using western blot, quantitative Real-Time PCR, and immunohistochemical showed that paeoniflorin could upregulate hepatic efflux transporters expression but downregulate hepatic uptake transporter expression. Meanwhile, paeoniflorin reduced bile acids synthesis by repressing cholesterol 7α-hydroxylase in hepatocytes. Paeoniflorin affected the above transporters and enzyme via activation of a nuclear receptor, farnesoid X receptor (FXR), which was recognized as a vital regulator for maintaining bile acid homeostasis. In conclusion, paeoniflorin alleviated EE-induced cholestasis and maintained bile acid homeostasis via FXR-mediated regulation of bile acids transporters and synthesis enzyme. The findings indicated that paeoniflorin might exert a potential therapeutic medicine for estrogen-induced cholestasis.

Project description:Bile acid (BA) biotransformation by gut bacteria impacts BA profile and signaling to nuclear receptors, such as the farnesoid X receptor (FXR) regulating glucose metabolism. Altered BA-FXR signaling was therefore investigated as a potential mechanism linking polyphenol-induced gut bacterial changes and improved glucose metabolism. Diabetic db/db were fed low-fat diet (LFD) or LFD supplemented with a proanthocyanidin-rich extract of grape polyphenols (LFD-GP) for 4 weeks. Metabolic phenotypes, serum BAs, gut microbiota composition, and gene expression markers relevant to gut barrier and glucose metabolism were assessed. Gut organoids were used to investigate effects of individual BAs on ileal FXR activity. Compared with LFD-fed controls, GP supplemented db/db mice showed improved glucose metabolism, decreased relative abundance of gut bacteria associated with production of secondary BAs (SBAs), and depleted serum levels of SBAs taurohyodeoxycholic acid (THDCA), ω-muricholic acid (ωMCA), and tauro-ω-muricholic acid (TωMCA). Serum levels of primary BAs (PBAs) increased, consistent with higher gene expression of PBA synthesis enzyme Cyp7a1. GP-induced BA changes associated with FXR inhibition as evidenced by reduced expression of FXR-responsive genes Shp, Fgf15, and Fabp6 in ileum tissue as well as hepatic Shp, which negatively regulates PBA synthesis. GP treatment did not affect expression of hepatic Fxr or expression of Abcb11, Slc51b, and Obp2a genes controlling BA transport. Ceramide biosynthesis genes Smpd3, Sptlc2, and Cers4 were decreased in liver and intestine suggesting lower tissue ceramides levels may contribute to improved glucose metabolism. THDCA, ωMCA, and TωMCA behaved as FXR agonists in ileal organoid experiments; therefore, their depletion in serum of GP-supplemented db/db and wild type (WT) mice was consistent with FXR inhibition. These data suggest that by altering the gut microbiota, GPs modify BA-FXR signaling pathways to promote glucoregulation.

Dataset Information

?-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis.

Publications

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

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