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Activation of FXR by bile acids in hepatic stellate cells plays a critical role in liver cirrhosis

ABSTRACT: Cirrhosis is a late stage of fibrosis impairing liver function. Genetic animal models for cirrhosis are lacking, and molecular mechanisms remain unknown. We report the first murine genetic model recapitulating human cirrhosis induced by hepatocyte-specific elimination of MCRS1, a member of NSL and INO80 chromatin-modifier complexes. MCRS1 loss in hepatocytes modulates the expression of bile acid (BA) transporters, with a pronounced NTCP downregulation, concentrating BAs in liver sinusoids, thereby activating hepatic stellate cell (HSC) via FXR. Consistently, genetic FXR ablation in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts HDAC1 from its H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays loss of nuclear MCRS1 and decreased NTCP expression. Thus, histone acetylation-mediated dysregulation of BA transporters, and consequently FXR activation by BAs in HSCs represent a central and universal signaling event in cirrhosis. The data is from single-nuclei RNA-seq of whole-liver collected during autopsy of 4 individuals with COVID-19 and PMI < 4.5 hours

ORGANISM(S): Homo sapiens

PROVIDER: GSE179548 | GEO | 2023/07/03

REPOSITORIES: GEO

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Project description:Bile acids (BAs) are a fundamental class of lipid emulsifying metabolites that are synthesized by hepatocytes, important for fat-soluble vitamin absorption, and maintained in vivo through enterohepatic circulation between the liver and ileum1. However, BAs are also lipophilic detergents and can be cytotoxic in enterohepatic tissues2. Whereas several nuclear receptors are known to prevent BA-driven toxicity in hepatocytes and intestinal enterocytes3, the mechanisms by which mucosal immune cells protect themselves from BAs in the ileum remains poorly understood. We recently reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to protect against BA toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here, we identify the BA- and xenobiotic-sensing nuclear receptor, constitutive androstane receptor (CAR/NR1I3), as a key regulator of MDR1 expression in mucosal Teff cells. CAR promotes large-scale transcriptional reprogramming of Teff cells in the small intestine lamina propria (siLP), which shares similarities with CAR-dependent gene expression in hepatocytes and involves the induction of both detoxifying enzymes and transporters, as well as anti-inflammatory cytokines, such as Il10. Accordingly, loss of CAR in Teff cells exacerbates, whereas pharmacologic CAR activation suppresses, BA-driven ileitis in T cell-reconstituted Rag1-/- mice. Further, CAR transcriptional activity is evident in human CD4+ T cells, but only in 4+7+CCR9+ Teff cells that are licensed for small bowel homing. In these cells, CAR activation also promotes cyto-protective and anti-inflammatory gene expression, including a core set of transcriptional targets that are similarly regulated by CAR in mouse mucosal Teff cells and hepatocytes. Together, these results suggest that mucosal T cells rely on CAR to activate a hepatocyte-like transcriptional response in the ileum that detoxifies BAs and safeguards immune homeostasis. Pharmacologic activation of this program may offer an unexpected strategy to treat small bowel Crohn’s disease.

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Activation of FXR by bile acids in hepatic stellate cells plays a critical role in liver cirrhosis

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