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Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration.

08:00 EDT 9th October 2018 | BioPortfolio

Summary of "Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration."

Non-alcoholic 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 signals from activated GPCRs, and modulate cell signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of Gα12 on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα12 level in mouse liver. Gα12 ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12 KO liver revealed that Gα12 signaling pathway regulated sirtuin 1 (SIRT1) and PPARα 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 Gα12 overexpression in hepatocytes. Mechanistically, Gα12 stabilized SIRT1 protein through transcriptional induction of USP22 via HIF-1α increase. Gα12 levels were markedly diminished in liver biopsies from NAFLD patients. Consistently, Gna12 KO mice fed high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Our results demonstrate that Gα12 regulates SIRT1-dependent mitochondrial respiration through HIF-1α-dependent USP22 induction, identifying Gα12 as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.

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This article was published in the following journal.

Name: The Journal of clinical investigation
ISSN: 1558-8238
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