Loss of β-catenin improves cholestatic injury through activation of bile acid detoxification and cholesterol metabolism

Primary sclerosing cholangitis (PSC) can result in retention of toxic bile acids (BA) leading to cell death, inflammation, and fibrosis. Lithocholic acid (LCA) is a BA associated with adverse clinical outcomes in PSC. We hypothesized that loss of β-catenin, which alleviates toxic BA accumulation, may reduce LCA-induced cholestasis. Liver-specific β-catenin knockout (KO) mice had fewer and smaller bile infarcts and decreased hepatobiliary injury compared to wild-type littermates after exposure to 0.6% LCA diet for 7 days. In the absence of β-catenin, xenobiotic pathways that detoxify bile were activated, resulting in decreased serum BA hydrophobicity in KO. Additionally, loss of β-catenin increased activation of the oxysterol-activated liver X receptor (LXR) in KO, resulting in activation of downstream targets that control cholesterol metabolism and transport in hepatocytes. Hepatocyte IL-33 expression was also reduced, which in turn decreased recruitment of disease-exacerbating type 2 innate lymphoid cells (ILC2). In conclusion, loss of β-catenin during LCA-induced cholestasis enhances xenobiotic- and LXR-mediated processes such as regulation of BA composition and cholesterol metabolism, and also alters the inflammatory response. These data demonstrate a newly-identified β-catenin-dependent mechanism that contributes to hepatic injury in patients with cholestasis. LCA activates PXR, which simultaneously prevents HNF binding to the Cyp7a1 promoter, downregulating expression of this gene and resulting in increased cholesterol accumulation, and binds to the Cyp3a11 and Cyp2b10 promoters, increasing expression of these genes and resulting in increased BA detoxification. When ;-catenin is absent, PXR activation is increased, as is HNF4 binding to the Cyp27a1 promoter, resulting in production of hydrophilic BA and accumulation of oxysterols. Oxysterols then activate LXR, which suppresses cholesterol synthesis, activates expression of genes involved in cholesterol and oxysterol efflux in hepatocytes, and represses expression of inflammatory genes in Kupffer cells.