期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 12, 页码 5587-5602出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI97831
关键词
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资金
- National Research Foundation of Korea (NRF) grant - Korea government [NRF-2018R1A2A1A05078694]
- Basic Science Research Program of the Ministry of Education [NRF-2018R1A6A3A11048112, NRF-2014R1A6A3A01054056]
- NIH/National Heart, Lung, and Blood Institute [T32HL134637]
- NIH [R01DK085252]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry for Health and Welfare of Korea [HI14C1135]
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 alpha(12) (G alpha(12)) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased G alpha(12) levels in mouse liver. G alpha(12) ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the G alpha(12)-signaling pathway regulated sirtuin 1 (SIRT1) and PPAR alpha, 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 alpha(12) overexpression in hepatocytes. Mechanistically, G alpha(12) stabilized SIRT1 protein through transcriptional induction of ubiquitinspecific peptidase 22 (USP22) via HIF-1 alpha increase. G alpha(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 alpha(12) regulates SIRT1-dependent mitochondrial respiration through HIF-1 alpha-dependent USP22 induction, identifying G alpha(12) as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.
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