12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration

Tae Hyun Kim, Yoon Mee Yang, Chang Yeob Han, Ja Hyun Koo, Hyunhee Oh, Su Sung Kim, Byoung Hoon You, Young Hee Choi, Tae Sik Park, Chang Ho Lee, Hitoshi Kurose, Mazen Noureddin, Ekihiro Seki, Yu-Jui Yvonne Wan, Cheol Soo Choi, Sang Geon Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5587-5602
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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Sirtuin 1
Fatty Liver
Ubiquitin
GTP-Binding Proteins
Respiration
Peptide Hydrolases
Obesity
Energy Metabolism
Liver
Fasting
Heterotrimeric GTP-Binding Proteins
Lentivirus
Peroxisome Proliferator-Activated Receptors
High Fat Diet
Microarray Analysis
Energy Intake
Oligonucleotide Array Sequence Analysis
Lipid Metabolism
Hepatocytes
Homeostasis

ASJC Scopus subject areas

  • Medicine(all)

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12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration. / 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.

In: Journal of Clinical Investigation, Vol. 128, No. 12, 03.12.2018, p. 5587-5602.

Research output: Contribution to journalArticle

Kim, TH, Yang, YM, Han, CY, Koo, JH, Oh, H, Kim, SS, You, BH, Choi, YH, Park, TS, Lee, CH, Kurose, H, Noureddin, M, Seki, E, Wan, Y-JY, Choi, CS & Kim, SG 2018, '12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration', Journal of Clinical Investigation, vol. 128, no. 12, pp. 5587-5602. https://doi.org/10.1172/JCI97831
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. / 12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 12. pp. 5587-5602.
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AU - Kim, Tae Hyun

AU - Yang, Yoon Mee

AU - Han, Chang Yeob

AU - Koo, Ja Hyun

AU - Oh, Hyunhee

AU - Kim, Su Sung

AU - You, Byoung Hoon

AU - Choi, Young Hee

AU - Park, Tae Sik

AU - Lee, Chang Ho

AU - Kurose, Hitoshi

AU - Noureddin, Mazen

AU - Seki, Ekihiro

AU - Wan, Yu-Jui Yvonne

AU - Choi, Cheol Soo

AU - Kim, Sang Geon

PY - 2018/12/3

Y1 - 2018/12/3

N2 - 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.

AB - 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.

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