Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration
Tae Hyun Kim, … , Cheol Soo Choi, Sang Geon Kim
Tae Hyun Kim, … , Cheol Soo Choi, Sang Geon Kim
Published October 9, 2018
Citation Information: J Clin Invest. 2018;128(12):5587-5602. https://doi.org/10.1172/JCI97831.
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Research Article Hepatology Metabolism

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.

Authors

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

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Figure 2

Gα12 regulation of mitochondrial respiration via SIRT1/PPARα network.

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Gα12 regulation of mitochondrial respiration via SIRT1/PPARα network. (A...
(A) PANTHER pathway analysis in the cDNA microarrays performed using RNA samples extracted from the livers of 8-week-old male WT or Gna12-KO mice that had been fasted overnight before sacrifice (n = 3/group). Percentage of number of genes that belong to respective pathway categories over total number of genes analyzed is shown. (B) GO analysis of major signaling pathways in cDNA microarrays using the DAVID bioinformatics database. (C) Heatmap of the genes associated with energy metabolism in the same cDNA microarrays used for A. The log2 ratios of Gna12-KO/WT were presented using heatmap (blue, underexpression; red, overexpression). (D) Core network analysis associated with the SIRT1/PPARα pathway. PPARα-associated genes affected by Gna12 KO are represented as colored circles and assigned to specific subcategories. Genes upregulated (red circles) or downregulated (blue circles) in the microarrays are shown for each subcategory. Line thickness represents the strength of evidence provided by the STRING database.