Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation

Abstract

Being activated by deacetylation, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has become an important regulator of metabolic-related diseases. The activation of Sirtuin 1 (Sirt1) by resveratrol was likely to deacetylate PGC-1α. However, the role of deacetylated PGC-1α in the alleviation of activated Sirt1 on type 2 diabetes mellitus (T2DM)-related fatty liver disease (FLD) remained unexplored. The aim of this study was to investigate the potential impact of Sirt1-mediated deacetylation of PGC-1α on T2DM-associated FLD and its underlying mechanisms. Our findings revealed that, along with the decreased Sirt1, the levels of acetylated PGC-1α were up-regulated in hepatocytes co-stimulated with high glucose (HG) and free fatty acids (FFA). Down-regulated Sirt1 inactivated PGC-1α by inhibiting its deacetylation, while activating Sirt1 improved hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α. However, the beneficial effects of Sirt1 activation on hepatic steatosis were inhibited by PGC-1α antagonist in vitro. Mechanistically, activating Sirt1 enhanced mitochondrial function by promoting PGC-1α activity, thereby facilitating hepatic fatty acid oxidation (FAO). In conclusion, Sirt1-mediated deacetylation of PGC-1α mitigated hepatic lipotoxicity by enhancing mitochondrial FAO, which contributed to the restoration of mitochondrial function in T2DM. The activation of Sirt1-mediated PGC-1α deacetylation might represent a promising therapeutic approach for T2DM-associated FLD.