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

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 All liver specimens were collected (under IRB approved protocols, appropriate consent and ethical standards) during autopsy of individuals with COVID-19. The samples include three male and one female (age 70-83 years) and the post-mortem incision time for autopsy was less than 4.5 h. Liver samples were processed in a biosafety cabinet equipped for working with COVID-19 . The tissue was dissociated and nuclei were seperated using the steps detailed in the 'Methods'. After counting, nuclei were immediately processed for droplet-based singe nuclei RNA sequencing (snRNA-seq). snRNA-seq library prep details are in 'Methods'. Single-nuclei RNA libraries were quantified using Tapestation D1000 screening tapes (Agilent, Santa Clara, CA) and Qbit HS DNA quantification kit (Thermo Fisher Scientific). Libraries were pooled equimolarly and quantified using quantitative PCR. Libraries were sequenced on a NovaSeq 6000 with S4 flow cell (Illumina, San Diego, CA) using paired end, single index sequencing. >>>Submitter states: Human raw sequencing data will be uploaded to controlled access database to meet institutional protocols.<<<