1. Academic Validation
  2. HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation

HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation

  • J Lipid Res. 2018 Feb;59(2):330-338. doi: 10.1194/jlr.M080382.
Xinchen Qiu 1 2 Jian Li 1 2 Sihan Lv 1 Jiamin Yu 1 Junkun Jiang 1 Jindong Yao 2 Yang Xiao 2 Bingxin Xu 2 Haiyan He 2 Fangfei Guo 2 Zhen-Ning Zhang 3 Chao Zhang 3 Bing Luan 4
Affiliations

Affiliations

  • 1 Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 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.
  • 3 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 bluan@tongji.edu.cn zhangchao@tongji.edu.cn znzhang@tongji.edu.cn.
  • 4 Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China bluan@tongji.edu.cn zhangchao@tongji.edu.cn znzhang@tongji.edu.cn.
Abstract

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.

Keywords

ER stress; HDAC5; PPARα; fasting signal; fatty acid oxidation.

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