G?12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) arises from mitochondrial dysfunction under sustained imbalance between energy intake and expenditure, but the underlying mechanisms controlling mitochondrial respiration have not been entirely understood. Heterotrimeric G proteins converge with activated GPCRs to modulate cell-signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of G protein ?12 (G?12) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased G?12 levels in mouse liver. G?12 ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the G?12-signaling pathway regulated sirtuin 1 (SIRT1) and PPAR?, which are responsible for mitochondrial respiration. Defective induction of SIRT1 upon fasting was observed in the liver of Gna12-KO mice, which was reversed by lentivirus-mediated G?12 overexpression in hepatocytes. Mechanistically, G?12 stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1? increase. G?12 levels were markedly diminished in liver biopsies from NAFLD patients. Consistently, Gna12-KO mice fed a high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Our results demonstrate that G?12 regulates SIRT1-dependent mitochondrial respiration through HIF-1?-dependent USP22 induction, identifying G?12 as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.

SUBMITTER: Kim TH 

PROVIDER: S-EPMC6264648 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature