HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation
Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520342358 |
| _version_ | 1819293978529366016 |
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| author | Xinchen Qiu Jian Li Sihan Lv Jiamin Yu Junkun Jiang Jindong Yao Yang Xiao Bingxin Xu Haiyan He Fangfei Guo Zhen-Ning Zhang Chao Zhang Bing Luan |
| author_facet | Xinchen Qiu Jian Li Sihan Lv Jiamin Yu Junkun Jiang Jindong Yao Yang Xiao Bingxin Xu Haiyan He Fangfei Guo Zhen-Ning Zhang Chao Zhang Bing Luan |
| author_sort | Xinchen Qiu |
| collection | DOAJ |
| description | Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARα and promotes transcriptional activity of PPARα. As a result, overexpression of HDAC5 but not PPARα binding-deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II-mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity-associated hepatic steatosis. |
| first_indexed | 2024-12-24T04:19:01Z |
| format | Article |
| id | doaj.art-74e4638e3fe049fdad55ed80bc7d940a |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-24T04:19:01Z |
| publishDate | 2018-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-74e4638e3fe049fdad55ed80bc7d940a2022-12-21T17:15:52ZengElsevierJournal of Lipid Research0022-22752018-02-01592330338HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidationXinchen Qiu0Jian Li1Sihan Lv2Jiamin Yu3Junkun Jiang4Jindong Yao5Yang Xiao6Bingxin Xu7Haiyan He8Fangfei Guo9Zhen-Ning Zhang10Chao Zhang11Bing Luan12Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaDepartment of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaDepartment of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, ChinaTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaTranslational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, ChinaTo whom correspondence should be addressed.; Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China; To whom correspondence should be addressed.To whom correspondence should be addressed.; Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China; To whom correspondence should be addressed.To whom correspondence should be addressed.; Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China; To whom correspondence should be addressed.Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARα and promotes transcriptional activity of PPARα. As a result, overexpression of HDAC5 but not PPARα binding-deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II-mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity-associated hepatic steatosis.http://www.sciencedirect.com/science/article/pii/S0022227520342358ER stressHDAC5PPARαfatty acid oxidationfasting signal |
| spellingShingle | Xinchen Qiu Jian Li Sihan Lv Jiamin Yu Junkun Jiang Jindong Yao Yang Xiao Bingxin Xu Haiyan He Fangfei Guo Zhen-Ning Zhang Chao Zhang Bing Luan HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation Journal of Lipid Research ER stress HDAC5 PPARα fatty acid oxidation fasting signal |
| title | HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation |
| title_full | HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation |
| title_fullStr | HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation |
| title_full_unstemmed | HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation |
| title_short | HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation |
| title_sort | hdac5 integrates er stress and fasting signals to regulate hepatic fatty acid oxidation |
| topic | ER stress HDAC5 PPARα fatty acid oxidation fasting signal |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520342358 |
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