Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism.
Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism.
复制标题
白藜芦醇通过 SIRT1/ATF6 依赖性机制改善肝脏中的脂滴积聚
DOI：
10.1159/000495898
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发表时间：
2018
影响因子：
--
通讯作者：
Mi Mantian
中科院分区：
文献类型：
--
作者：
Zhou Rui;Yi Long;Ye Xikun;Zeng Xianglong;Liu Kai;Qin Yu;Zhang Qianyong;Mi Mantian
背景/目的脂滴是一种在能量过剩时储存中性脂类的动态细胞器，其在肝脏中的积累增加与肝脏脂肪变性密切相关。我们以前的研究表明，补充白藜芦醇(RSV)可以改善肝脏脂肪变性，但其机制，特别是与LD蓄积有关的机制尚未阐明。方法采用高脂饮食(HFD)和棕榈酸分别诱导小鼠肝脏和肝细胞脂肪变性。分析了RSV在体内和体外对LD积累的影响。用定量逆转录聚合酶链式反应和免疫印迹法检测呼吸道合胞病毒对LD相关基因(ATF6、FSP2 7β/CIDEC、CREBH和PLIN1)表达水平的影响，然后分别用小干扰RNA或高表达的质粒检测KD、SIRT1和ATF6的过表达。采用双荧光素酶报告实验、染色质免疫沉淀实验、免疫共沉淀实验和邻近连接实验研究SIRT1与ATF6的转录调控机制及可能的相互作用。结果在HFD诱导的脂肪变性过程中，肝和肝细胞中LDS的积聚分别显著增加，而RSV可显著抑制LDS在肝细胞中的积聚。RSV显著激活了SIRT1的表达，降低了与LD积累相关的ATF6、Fsp2 7β/CIDEC、CREBH和PLIN1的表达水平。有趣的是，RSV对肝细胞中LD积累的抑制作用和相关基因的表达分别被SIRT1沉默或过度表达所取消或加强。反之，过表达的ATF6或ATF6 siRNA分别可消除或加重RSV在肝细胞中的作用。此外，我们还发现RSV显著刺激了SIRT1的表达，随后ATF6的去乙酰化和失活增加，导致与SIRT1启动子区域结合的SIRT1转录的正反馈环。结论综上所述，这些发现表明补充RSV通过改善LDS的积累来改善肝脏脂肪变性，这可能部分是通过SIRT1/ATF6依赖的机制来调节的。
Background/AimsLipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated.MethodsA high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6.ResultsThere was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region.ConclusionTaken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism.