Hepatic Sirt2-PARP1-HMGB1 axis promotes exercise-mediated amelioration of MASH in mice

Exercise is an effective non-pharmacological strategy for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanism needs further investigation. Sirtuin 2 (Sirt2) is a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase that is expressed in multiple tissues, including the liver, whose role in MASH is not well defined. In our study, exercise induces hepatic Sirt2 expression through the DNA demethylation on the Sirt2 gene promoter mediated by α-ketoglutaric acid (α-KG)/ten-eleven translocation (TET) enzymes axis. Hepatocyte-specific knockout of Sirt2 (Sirt2^LKO) increases hepatic lipid accumulation, cell death, inflammation, and fibrosis in MASH diet-fed mice and reduces the protective effects of exercise against MASH, while hepatocyte-specific overexpression of Sirt2 works in concert with exercise to alleviate MASH. Mechanistically, Sirt2 promotes deacetylation and proteasomal degradation of poly (ADP-ribose) polymerase 1 (PARP1) in hepatocytes. This decreases polyADP-ribosylation (PAR) and acetylation of high mobility group box 1 (HMGB1), which inhibits HMGB1 nuclei-to-cytosol translocation and secretion from hepatocytes to attenuate free fatty acids (FFAs)-induced hepatocyte injury and blunts dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells (HSCs). Therefore, by regulating the hepatic PARP1/HMGB1 pathway, Sirt2 acts as a downstream effector of exercise to alleviate MASH.