Peroxisome proliferator-activated receptor γ coactivator 1α maintains NAD + bioavailability protecting against steatohepatitis

Abstract Hepatic metabolic derangements are pivotal incidences in the occurrence of hepatic steatosis, inflammation, and fibrosis. Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α), a master regulator that mediates adipose metabolism and mitochondrial biogenesis, its role in hepatic steatosis and progression to steatohepatitis remains elusive. By surveying genomic data on nonalcoholic steatohepatitis (NASH) patients available in the Gene Expression Omnibus, we found that PGC-1α was significantly down-regulated compared to healthy controls, implicating the restoration of PGC-1α may ameliorate the hepatopathy. Using a hepatocyte-specific PGC-1α overexpression (LivPGC1α) mouse model, we demonstrated that PGC-1α attenuated hepatic steatosis induced by methionine-choline deficient diet (MCD). Biochemical measurements and histological examination indicated less inflammatory infiltration, collagen deposition, NF-kB activation, and less lipid accumulation in LivPGC1α liver fed MCD. Further analyses indicated that the NAD +-dependent deacetylase sirtuin 2 (SIRT2) interacted with and deacetylated PGC-1α. Congruently, ablation of SIRT2 accelerated the NASH progression in mice fed MCD, while NAD + repletion via its precursor mimicked the beneficial effect of PGC-1α overexpression and was sufficient to alleviate NASH in mice. These findings indicate that hepatic-specific overexpression of PGC-1α exerts a beneficial role in the regulation of steatohepatitis and that pharmacological activation of the SIRT2-PGC-1α-NAD + axis may help to treat NASH.