Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration
| Autor: | Tae Sik Park, Chang Yeob Han, Young Hee Choi, Cheol Soo Choi, Byoung Hoon You, Tae Hyun Kim, Ekihiro Seki, Su Sung Kim, Chang Ho Lee, Yoon Mee Yang, Mazen Noureddin, Yu Jui Yvonne Wan, Hitoshi Kurose, Ja Hyun Koo, Hyunhee Oh, Sang Geon Kim |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty G protein Mitochondria Liver GTP-Binding Protein alpha Subunits G12-G13 Mice 03 medical and health sciences Oxygen Consumption 0302 clinical medicine Sirtuin 1 Heterotrimeric G protein Internal medicine Endopeptidases Nonalcoholic fatty liver disease medicine Animals Humans Obesity Beta oxidation G protein-coupled receptor Mice Knockout biology Chemistry Microarray analysis techniques General Medicine Metabolism medicine.disease Dietary Fats Fatty Liver 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis Hepatocytes biology.protein Energy Metabolism Ubiquitin Thiolesterase Signal Transduction Research Article |
| Zdroj: | Journal of Clinical Investigation. 128:5587-5602 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci97831 |
| Popis: | 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 α(12) (Gα(12)) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα(12) levels in mouse liver. Gα(12) ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the Gα(12)-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 Gα(12) overexpression in hepatocytes. Mechanistically, Gα(12) stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1α increase. Gα(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 Gα(12) regulates SIRT1-dependent mitochondrial respiration through HIF-1α–dependent USP22 induction, identifying Gα(12) as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure. |
| Databáze: | OpenAIRE |
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