SREBP2 links ACSS2-dependent acetyl-CoA biosynthesis to metaboloepigenetic activation of hepatic stellate cells and liver fibrosis.

Aberrant liver fibrosis is frequently observed in and contributes to the pathogenesis of end-stage liver diseases including cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSCs) trans-differentiate into ECM-producing myofibroblasts to mediate liver fibrosis. In the present study we investigated the role of sterol response element binding protein 2 (SREBP2) in this process focusing on epigenetic mechanism and translational potential. We report that HSC-specific deletion or myofibroblast-restricted SREBP2 depletion attenuated liver fibrosis in mice. Integrated transcriptomic analysis combining RNA-seq and CUT&Tag-seq identified acyl-coenzyme A synthetase short-chain family member 2 (ACSS2) as a novel SREBP2 target; SREBP2 directly bound to the ACSS2 promoter to activate ACSS2 transcription. Over-expression of ectopic ACSS2 partially rescued the deficiency of HSC-myofibroblast transition when SREBP2 was depleted. In contrast, ACSS2 deletion in HSCs or myofibroblasts ameliorated liver fibrosis in mice. Mechanistically, SREBP2-dependent ACSS2 trans-activation stimulated histone H3K9/H3K27 acetylation necessary for the expression of pro-fibrogenic genes in HSCs. Importantly, a small-molecule ACSS2 inhibitor (ACSS2i) mitigated liver fibrosis in mice. Finally, relevance of the SREBP2-ACSS2 axis was validated in biopsy specimens from patients with chronic liver disease. In conclusion, our data uncover a previously unappreciated role for SREBP2 in HSC activation and provide proof-of-concept for targeting ACSS2 in the intervention of liver fibrosis.