G alpha(12) ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration
- Authors
- Kim, TH (Kim, Tae Hyun); Yang, YM (Yang, Yoon Mee); Han, CY (Han, Chang Yeob); Koo, JH (Koo, Ja Hyun); Oh, H (Oh, Hyunhee); Kim, SS (Kim, Su Sung); You, BH (You, Byoung Hoon); Choi, YH (Choi, Young Hee); Park, TS (Park, Tae-Sik); Lee, CH (Lee, Chang Ho); Kurose, H (Kurose, Hitoshi); Noureddin, M (Noureddin, Mazen; Seki, E (Seki, Ekihiro); Wan, YJY (Wan, Yu-Jui Yvonne); Choi, CS (Choi, Cheol Soo); Kim, SG (Kim, Sang Geon)...Mor
- Issue Date
- Dec-2018
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Citation
- JOURNAL OF CLINICAL INVESTIGATION, v.128, no.12, pp 5587 - 5602
- Pages
- 16
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Volume
- 128
- Number
- 12
- Start Page
- 5587
- End Page
- 5602
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/159351
- DOI
- 10.1172/JCI97831
- ISSN
- 0021-9738
1558-8238
- 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 suscepti
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