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Targeting the chromatin remodeler BAZ2B mitigates liver aging and fibrosis

ABSTRACT: Increasing age enhances the liver's vulnerability to nonalcoholic steatohepatitis (NASH) with fibrosis. Unraveling the intricate molecular relationship among aging, cellular senescence, and NASH is critical for developing effective treatments, yet it remains a daunting challenge. Here we report a vital epigenetic mechanism that links liver aging to NASH fibrosis. We find that up-regulation of a chromatin remodeler BAZ2B in a subpopulation of hepatocytes contributes to the pathological progression of NASH in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b rejuvenates hepatic cells and limits diet-induced steatohepatitis and liver fibrosis via preserving the peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aging and NASH mouse livers. Mechanistically, Baz2b down-regulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Our study thus unravels the BAZ2B-PPARα-lipid-metabolism signal axis as a key pathway linking liver aging to NASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for hepatic fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE280663 | GEO | 2025/03/12

REPOSITORIES: GEO

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