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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 Article has an altmetric score of 1

Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration

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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 4

Lack of fasting induction of SIRT1 by Gna12 KO.

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Lack of fasting induction of SIRT1 by Gna12 KO.
(A) Abrogation of SIRT1 ...
(A) Abrogation of SIRT1 and CPT1 induction upon fasting by Gna12 KO. Immunoblottings for SIRT1 and CPT1 were performed and quantified on the liver homogenates from 12-week-old mice fed ad libitum, followed by fasting and refeeding for 24 hours (n = 4–5/group). (B) qRT-PCR assays for Acadl and Acadm in the liver (n = 5/group). (C) Effect of hepatic Gα12 gene knockdown on fasting induction of SIRT1. Immunoblottings for SIRT1 and CPT1 (center) in the liver homogenates and SIRT1 quantification (far right). Mice at 8 weeks of age were subjected to hydrodynamic injection with the plasmid-expressing sh-Gα12 or control (sh-Luci) (n = 4–6/group) (left). Third panel shows qRT-PCR assay for Gna12 in the liver (n = 4/group). (D) Representative H&E staining (left) and hepatic TG contents (right) from the same mice as in C (n = 4–6/group). Scale bars: 100 μm. (E) Effect of hepatocyte-specific Gα12 overexpression on fasting induction of SIRT1. Eight-week-old WT or Gna12-KO mice were injected with Lv-Gα12alb (or control) via the tail vein (left). Immunoblottings for SIRT1 and CPT1 were done on the liver homogenates (center) and SIRT1 quantification (right). Mice were subjected to fasting as in A. (n = 4/group). Third panel shows qRT-PCR assay for Gna12 in the liver (n = 7–10/group). (F) Representative H&E staining (left) and hepatic TG contents (right) from mice as described in E (n = 4–6/group). For E and F, only fasted groups were analyzed for ease of data presentation. Scale bars: 100 μm. Values represent mean ± SEM. Data were analyzed by 2-tailed Student’s t test (C and E, mRNA levels) or ANOVA followed by LSD (A and D) or Bonferroni’s (B, C, E, and F) post hoc tests. For A as well as C and E (protein levels), the blots in each panel were run in parallel using the same samples and β-actin was used as a normalization control for densitometric analysis.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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