G alpha(12) ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration
- Title
- G alpha(12) ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration
- Author
- 이창호
- Keywords
- HETEROTRIMERIC G-PROTEINS; ACTIVATED RECEPTOR-ALPHA; N-TERMINAL KINASE; HEPATIC STEATOSIS; FATTY LIVER; GLUCOSE-INTOLERANCE; ADENOSINE RECEPTORS; SIRT1; HYPOXIA; METABOLISM
- Issue Date
- 2018-12
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Citation
- JOURNAL OF CLINICAL INVESTIGATION, v. 128, no. 12, page. 5587-5602
- 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 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.
- URI
- https://www.jci.org/articles/view/97831https://repository.hanyang.ac.kr/handle/20.500.11754/121063
- ISSN
- 0021-9738; 1558-8238
- DOI
- 10.1172/JCI97831
- Appears in Collections:
- COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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