한빛사 논문
Amanda Garrido1,†, Eunjeong Kim1,†, Ana Teijeiro1, Paula Sánchez Sánchez1, Rosa Gallo1, Ajay Nair2, María Matamala Montoya1, Cristian Perna3, Guillermo P. Vicent4, Javier Muñoz5,6, Ramón Campos-Olivas7, Johannes C. Melms8, Benjamin Izar8, Robert F. Schwabe2, Nabil Djouder1,*
1Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
2Department of Medicine, Columbia University, New York, NY 10032, USA
3Department of Pathology, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, 28034, Spain
4Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Científicas (IBMB-CSIC), Barcelona, 08028, Spain
5Biotechnology Programme, Proteomics Core Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
6Present address: Biocruces Bizkaia Health Research Institute. Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
7Structural Biology Programme, Spectroscopyand Nuclear Magnetic Resonance Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
8Department of Medicine, Division of Hematology and Oncology, Irving Medical Center, Columbia University, New York, NY 10032, USA
†Equal contribution.
*Corresponding author.
Abstract
Background & Aims
Owing to the lack of genetic animal models that adequately recreate key clinical characteristics of cirrhosis, the molecular pathogenesis of cirrhosis has been poorly characterized, and treatments remain limited. Hence, we aimed to better elucidate the pathological mechanisms of cirrhosis using a novel murine model.
Methods
We report on the first murine genetic model mimicking human cirrhosis induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of non-specific lethal (NSL) and INO80 chromatin-modifier complexes. Using this genetic tool with other mouse models, cell culture and human samples, combined with quantitative proteomics, single nuclei/cell RNA sequencing and chromatin immunoprecipitation assays, we investigated mechanisms of cirrhosis.
Results
MCRS1 loss in mouse hepatocytes modulates the expression of bile acid (BA) transporters – with a pronounced downregulation of Na+-taurocholate cotransporting polypeptide (NTCP) – concentrating BAs in sinusoids and thereby activating hepatic stellate cells (HSCs) via the farnesoid X receptor (FXR), which is predominantly expressed in human and mouse HSCs. Consistently, re-expression of NTCP in mice reduces cirrhosis, and genetic ablation of FXR in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts histone deacetylase 1 from its histone H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays decreased nuclear MCRS1 and NTCP expression.
Conclusions
Our data reveal a previously unrecognized function of MCRS1 as a critical histone acetylation regulator, maintaining gene expression and liver homeostasis. MCRS1 loss induces acetylation of BA transporter genes, perturbation of BA flow, and consequently, FXR activation in HSCs. This axis represents a central and universal signaling event in cirrhosis, which has significant implications for cirrhosis treatment.
Lay summary
By genetic ablation of MCRS1 in mouse hepatocytes, we generate the first genetic mouse model of cirrhosis that recapitulates human features. Herein, we demonstrate that the activation of the bile acid/FXR axis in liver fibroblasts is key in cirrhosis development.
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