3 years ago

HDAC5 Integrates ER Stress and Fasting Signals to Regulate Hepatic Fatty Acid Oxidation.

Fangfei Guo, Bingxin Xu, Bing Luan, Junkun Jiang, Chao Zhang, Jiamin Yu, Haiyan He, Yang Xiao, Jindong Yao, Jian Li, Xinchen Qiu, Zhen-Ning Zhang, Sihan Lv
Disregulation of fatty acid oxidation, one of the major mechanisms to maintain hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced ER stress contributes 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 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, while RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via CaMKII-mediated phosphorylation of HDAC5. Most importantly, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression, and protects against hepatic steatosis in high-fat-diet (HFD) fed mice. Taken together, 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.

Publisher URL: http://doi.org/10.1194/jlr.M080382

DOI: 10.1194/jlr.M080382

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