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-gamma coactivator-1 alpha (PGC-1 alpha) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC-1 alpha and steatohepatitis. Methods: We measured the hepatic expression of Pgc-1 alpha 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-1 alpha 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-1 alpha is strongly reduced in MASH, in both humans and mice. Moreover, the hepatic ablation of Pgc-1 alpha promotes a considerable reduction of the hepatic mitochondrial respiratory capacity, setting up a bioenergetic harmful environment for liver diseases. Indeed, the lack of Pgc-1 alpha decreases mitochondrial function and increases inflammation, fibrosis and oxidative stress in the scenario of MASH. Intriguingly, this profibrotic phenotype is not linked with obesity, insulin resistance and lipid disbalance. Conclusions: In a MASH model the hepatic ablation of Pgc-1 alpha drives fibrosis independently from lipid and glucose metabolism. These results add a novel mechanistic piece to the puzzle of the specific and crucial role of mitochondrial function in MASH development.