Full metadata record
DC Field | Value | Language |
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dc.contributor.author | 이창호 | - |
dc.date.accessioned | 2019-12-10T17:07:48Z | - |
dc.date.available | 2019-12-10T17:07:48Z | - |
dc.date.issued | 2018-12 | - |
dc.identifier.citation | JOURNAL OF CLINICAL INVESTIGATION, v. 128, no. 12, page. 5587-5602 | en_US |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.issn | 1558-8238 | - |
dc.identifier.uri | https://www.jci.org/articles/view/97831 | - |
dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/121063 | - |
dc.description.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. | en_US |
dc.description.sponsorship | 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 G alpha<INF>12</INF>QL (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). | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | en_US |
dc.subject | HETEROTRIMERIC G-PROTEINS | en_US |
dc.subject | ACTIVATED RECEPTOR-ALPHA | en_US |
dc.subject | N-TERMINAL KINASE | en_US |
dc.subject | HEPATIC STEATOSIS | en_US |
dc.subject | FATTY LIVER | en_US |
dc.subject | GLUCOSE-INTOLERANCE | en_US |
dc.subject | ADENOSINE RECEPTORS | en_US |
dc.subject | SIRT1 | en_US |
dc.subject | HYPOXIA | en_US |
dc.subject | METABOLISM | en_US |
dc.title | G alpha(12) ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration | en_US |
dc.type | Article | en_US |
dc.relation.no | 12 | - |
dc.relation.volume | 128 | - |
dc.identifier.doi | 10.1172/JCI97831 | - |
dc.relation.page | 5587-5602 | - |
dc.relation.journal | JOURNAL OF CLINICAL INVESTIGATION | - |
dc.contributor.googleauthor | Kim, Tae Hyun | - |
dc.contributor.googleauthor | Yang, Yoon Mee | - |
dc.contributor.googleauthor | Han, Chang Yeob | - |
dc.contributor.googleauthor | Koo, Ja Hyun | - |
dc.contributor.googleauthor | Oh, Hyunhee | - |
dc.contributor.googleauthor | Kim, Su Sung | - |
dc.contributor.googleauthor | You, Byoung Hoon | - |
dc.contributor.googleauthor | Choi, Young Hee | - |
dc.contributor.googleauthor | Park, Tae-Sik | - |
dc.contributor.googleauthor | Lee, Chang Ho | - |
dc.relation.code | 2018001762 | - |
dc.sector.campus | S | - |
dc.sector.daehak | COLLEGE OF MEDICINE[S] | - |
dc.sector.department | DEPARTMENT OF MEDICINE | - |
dc.identifier.pid | jennysue | - |
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