| First Author | Kim TH | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 12 | Pages | 5587-5602 |
| PubMed ID | 30300140 | Mgi Jnum | J:270513 |
| Mgi Id | MGI:6276446 | Doi | 10.1172/JCI97831 |
| Citation | Kim TH, et al. (2018) Galpha12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration. J Clin Invest 128(12):5587-5602 |
| abstractText | 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 alpha12 (Galpha12) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Galpha12 levels in mouse liver. Galpha12 ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the Galpha12-signaling pathway regulated sirtuin 1 (SIRT1) and PPARalpha, 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 Galpha12 overexpression in hepatocytes. Mechanistically, Galpha12 stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1alpha increase. Galpha12 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 Galpha12 regulates SIRT1-dependent mitochondrial respiration through HIF-1alpha-dependent USP22 induction, identifying Galpha12 as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure. |
