Hepatic‐specific Pgc‐1α ablation drives fibrosis in a MASH model

Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a growing cause of chronic liver disease, characterized by fat accumulation, inflammation and fibrosis, which development depends on mitochondrial dysfunction and oxidative stress. Highly expressed in the liver during fasting, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC-1α and steatohepatitis. Methods: We measured the hepatic expression of Pgc-1α in both MASH patients and wild-type mice fed a western diet (WD) inducing steatosis and fibrosis. We then generated a pure C57BL6/J strain loss of function mouse model in which Pgc-1α is selectively deleted in the liver and we fed these mice with a WD supplemented with sugar water that accurately mimics human MASH. Results: We observed that the hepatic expression of Pgc-1α is strongly reduce...