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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/97831http://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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