Deletion of steroid receptor coactivator-3 gene ameliorates hepatic steatosis
Deletion of steroid receptor coactivator-3 gene ameliorates hepatic steatosis
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类固醇受体辅激活因子 3 基因的缺失可改善肝脂肪变性。
DOI：
10.1016/j.jhep.2010.11.022
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发表时间：
2011-08-01
影响因子：
25.7
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Ma, Xinran;Xu, Lingyan;Ning, Guang
背景与目的：过量膳食脂肪可引起肝脏脂肪变性，可发展为脂肪性肝炎和肝硬变等严重肝病。类固醇受体辅活化子-3(SRC-3)是p160辅活化子家族的成员之一，被认为是脂肪生成和能量平衡的关键调节因子。我们试图确定SRC-3对肝脏脂肪变性的影响及其机制。方法：在HepG2细胞中评价siRNA介导的SRC-3沉默对肝脏脂质堆积的影响。并对SRC-3调节肝脂代谢的分子机制进行了探讨。此外，我们还观察了SRC-3对SRC-3缺陷小鼠肝脏脂肪变性的影响。结果：在本研究中，我们报道了SRC-3消融减少了棕榈酸诱导的HepG2细胞中的脂质积聚。此外，SRC-3的缺失可以改善高脂饮食(HFD)小鼠的肝脏脂肪变性和炎症反应。这些代谢的改善可能是由于鸡卵清蛋白上游启动子转录因子II(COUP-TFII)表达的减少和随后过氧化体增殖物激活受体α(PPARα)水平的上升所致。在分子水平上，SRC-3与维甲酸受体α(RARα)相互作用，激活全反式维甲酸(ARTA)作用下COUP-TFII的表达。结论：SRC-3在调节肝脏脂质代谢中发挥重要作用，并提供了可能的新的内部机制。(C)2011年由Elsevier B.V.代表欧洲肝脏研究协会出版。
Background & aims: Excess dietary fat can cause hepatic steatosis, which can progress into severe liver disorders including steatohepatitis and cirrhosis. Steroid receptor coactivator-3 (SRC-3), a member of the p160 coactivator family, is reported as a key regulator of adipogenesis and energy homeostasis. We sought to determine the influence of SRC-3 on hepatic steatosis and the mechanism beneath.Methods: The influence of siRNA-mediated SRC-3 silencing on hepatic lipid accumulation was assessed in HepG2 cells. The molecular mechanism of SRC-3 regulation of hepatic lipid metabolism was also studied. Moreover, the effect of SRC-3 ablation on hepatic steatosis was examined in SRC-3 deficient mice.Results: In this study, we report that SRC-3 ablation reduces palmitic acid-induced lipid accumulation in HepG2 cells. Moreover, deletion of SRC-3 ameliorates hepatic steatosis and inflammation response in mice fed a high fat diet (HFD). These metabolic improvements can presumably be explained by the reduction in chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) expression and the subsequent elevation in peroxisome proliferator-activated receptor alpha (PPAR alpha) level. At the molecular level, SRC-3 interacts with retinoic receptor a (RAR alpha) to activate COUP-TFII expression under all-trans retinoic acid (ARTA) treatment.Conclusions: These findings indicate a crucial role for SRC-3 in regulating hepatic lipid metabolism and provide the possible novel inner mechanisms. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.