G alpha(12) ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration
- Authors
- Kim, Tae Hyun; Yang, Yoon Mee; Han, Chang Yeob; Koo, Ja Hyun; Oh, Hyunhee; Kim, Su Sung; You, Byoung Hoon; Choi, Young Hee; Park, Tae-Sik; Lee, Chang Ho; Kurose, Hitoshi; Noureddin, Mazen; Seki, Ekihiro; Wan, Yu-Jui Yvonne; Choi, Cheol Soo; Kim, Sang Geon
- Issue Date
- 3-Dec-2018
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Citation
- JOURNAL OF CLINICAL INVESTIGATION, v.128, no.12, pp.5587 - 5602
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Volume
- 128
- Number
- 12
- Start Page
- 5587
- End Page
- 5602
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/2961
- DOI
- 10.1172/JCI97831
- ISSN
- 0021-9738
- 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.
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Collections - 의과대학 > 의예과 > 1. Journal Articles
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