@article{447d0aa9509b47a7978597df1cf5641d,
title = "Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration",
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 α12 (Gα12) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα12 levels in mouse liver. Gα12 ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the Gα12-signaling pathway regulated sirtuin 1 (SIRT1) and PPARα, 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 Gα12 overexpression in hepatocytes. Mechanistically, Gα12 stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1α increase. Gα12 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 Gα12 regulates SIRT1-dependent mitochondrial respiration through HIF-1α–dependent USP22 induction, identifying Gα12 as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.",
author = "Kim, {Tae Hyun} and Yang, {Yoon Mee} and Han, {Chang Yeob} and Koo, {Ja Hyun} and Hyunhee Oh and Kim, {Su Sung} and You, {Byoung Hoon} and Choi, {Young Hee} and Park, {Tae Sik} and Lee, {Chang Ho} and Hitoshi Kurose and Mazen Noureddin and Ekihiro Seki and Wan, {Yu Jui Yvonne} and Choi, {Cheol Soo} and Kim, {Sang Geon}",
note = "Funding Information: We thank Melvin I. Simon (California Institute of Technology, Pasadena, California, USA) for the Gna12-KO mice and MEF cells, Patrick J. Casey (Duke University Medical Center, Durham, North Carolina, USA) for the adenovirus encoding mouse Gα12QL (Q229L), Richard D. Palmiter (University of Washington, Seattle, Washington, USA) for the mouse albumin enhancer/promoter (NB) construct, and Junichi Sadoshima (Rutgers New Jersey Medical School, Newark, New Jersey, USA) for the adenovirus encoding mouse SIRT1. We thank Yu-Jui Yvonne Wan, Ekihiro Seki, and Mazen Noureddin for providing human NAFLD liver samples from the University of Kansas Medical Center, Liver Tissue Bank (cohort no. 1 for YJYW) and Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Center (cohort no. 2 for ES and MN). Min6 cells were kindly provided by Eun Young Park (Mokpo National University, Mokpo, South Korea). This research was supported mainly by a National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2018R1A2A1A05078694 to SGK). THK was supported partly by the Basic Science Research Program of the Ministry of Education (NRF-2018R1A6A3A11048112). YMY was supported partly by the Basic Science Research Program of the Ministry of Education (NRF-2014R1A6A3A01054056) and by the NIH/National Heart, Lung, and Blood Institute (T32HL134637). ES and MN were supported in part by the NIH (R01DK085252). HO and CSC were supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry for Health and Welfare of Korea (HI14C1135). Publisher Copyright: Copyright 2018, American Society for Clinical Investigation.",
year = "2018",
month = dec,
day = "3",
doi = "10.1172/JCI97831",
language = "English",
volume = "128",
pages = "5587--5602",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",
}