Phosphorylated heat shock protein 27 promotes lipid clearance in hepatic cells through interacting with STAT3 and activating autophagy
Phosphorylated heat shock protein 27 promotes lipid clearance in hepatic cells through interacting with STAT3 and activating autophagy
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磷酸化热休克蛋白27通过与STAT3相互作用并激活自噬促进肝细胞脂质清除
DOI：
10.1016/j.cellsig.2016.05.008
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发表时间：
2016
影响因子：
4.8
通讯作者：
Yin ZM
中科院分区：
文献类型：
--
作者：
Shen Lei;Qi Zhilin;Zhu Yanyan;Song Xiaomeng;Xuan Chunxia;Ben Peiling;Lan Lei;Yin Zhimin;Luo Lan;Qi Zhilin;Lan L;Luo L;Yin ZM
非酒精性脂肪性肝病（NAFLD）已成为世界范围内主要的肝脏疾病。最近，有几项研究。已发现自噬的激活可减轻肝脂肪变性。热休克蛋白27 （Hsp27）。参与对各种刺激的自噬。在这项研究中，我们证明了磷酸化。Hsp27刺激自噬和脂滴清除，并与STAT3相互作用。体内研究表明。高脂饲料（HFD）喂养增加Hsp25（小鼠Hsp27同源蛋白）磷酸化和自噬。老鼠的肝脏。抑制Hsp25磷酸化可加重hfd诱导的小鼠肝脂肪变性。体外。研究表明，敲低Hsp27可增强棕榈酸盐诱导的肝细胞脂质过载。KRIBB3处理和Hsp27-3A（非磷酸化）过表达，但被Hsp27-WT阻止。（野生型）和Hsp27-3D（拟磷）过表达。机理分析表明，棕榈酸盐。能诱导Hsp27磷酸化，促进棕榈酸诱导的自噬。磷酸化的hsp27在棕榈酸盐处理下与STAT3相互作用，破坏STAT3/PKR复合物，促进。pkr依赖性eIF2α磷酸化，从而刺激自噬。总之，我们的研究提供了磷酸化的Hsp27促进肝脏脂质清除的新机制，并提出了新的见解。用于治疗脂肪变性疾病，如非酒精性脂肪性肝病（NAFLD）。
Nonalcoholic fatty liver disease (NAFLD) has become the major liver diseaseworldwide. Recently, several studies.have identified that the activation of autophagy attenuates hepatic steatosis. Heat shock protein 27 (Hsp27) is.involved in autophagy in response to various stimuli. In this study, we demonstrate that phosphorylated.Hsp27 stimulates autophagy and lipid droplet clearance and interacts with STAT3. In vivo study showed that.high fat diet (HFD) feeding increased Hsp25 (mouse orthology of Hsp27) phosphorylation and autophagy in.mouse livers. Inhibition of Hsp25 phosphorylation exacerbated HFD-induced hepatic steatosis in mice. In vitro.study showed that palmitate-induced lipid overload in hepatic cells was enhanced by Hsp27 knockdown,.KRIBB3 treatment and Hsp27-3A (non-phosphorylatable) overexpression but was prevented by Hsp27-WT.(wild type) and Hsp27-3D (phosphomimetic) overexpression. Mechanismanalysis demonstrated that palmitate.could induce Hsp27 phosphorylation which promoted palmitate-induced autophagy. Phosphorylated Hsp27.interacted with STAT3 in response to palmitate treatment, and disrupted the STAT3/PKR complexes, facilitated.PKR-dependent eIF2α phosphorylation, and thus stimulated autophagy. To conclude, our study provides a.novel mechanism by which the phosphorylated Hsp27 promotes hepatic lipid clearance and suggests a new insight.for therapy of steatotic diseases such as nonalcoholic fatty liver disease (NAFLD).