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
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HDAC5 整合 ER 应激和禁食信号来调节肝脏脂肪酸氧化。
DOI：
10.1194/jlr.m080382
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发表时间：
2018-02-01
影响因子：
6.5
通讯作者：
Luan, Bing
中科院分区：
文献类型：
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作者：
Qiu, Xinchen;Li, Jian;Luan, Bing
脂肪酸氧化的失调是在禁食条件下维持肝脏脂质平衡的主要机制之一，导致肝脏脂肪变性。虽然肥胖和2型糖尿病诱导的内质网应激导致肝脏脂肪变性，但内质网应激如何调节脂肪酸氧化在很大程度上尚不清楚。在这里，我们发现空腹高血糖素刺激组蛋白脱乙酰基酶5(HDAC5)的去磷酸化和核转位，在那里它与PPARα相互作用并促进PPARα的转录活性。结果表明，HDAC5过表达，而PPAR没有过表达。肝脏中结合缺陷的HDAC5改善脂质平衡，而RNAi介导的HDAC5基因敲除会加重肝脏脂肪变性。内质网应激通过钙/钙调蛋白依赖的蛋白激酶II介导的HDAC5的磷酸化来抑制脂肪酸氧化基因的表达。最重要的是，肝脏过度表达磷酸化缺陷突变体HDAC5 2SA促进了肝脏脂肪酸氧化基因的表达，并防止了高脂饮食小鼠的肝脏脂肪变性。我们通过禁食和内质网应激信号确定HDAC5是一种新的肝脏脂肪酸氧化介质，促进HDAC5去磷酸化的策略可能成为治疗肥胖相关性肝脏脂肪变性的新工具。
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 PPAR alpha and promotes transcriptional activity of PPAR alpha. As a result, overexpression of HDAC5 but not PPAR. 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.