GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway.
GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway.
复制标题
GPR40 激动剂通过激活 AMPK 通路改善肝脏 X 受体诱导的肝脏脂质积累
DOI：
10.1038/srep25237
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发表时间：
2016-04-28
影响因子：
4.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Li M;Meng X;Xu J;Huang X;Li H;Li G;Wang S;Man Y;Tang W;Li J
肝脏脂肪变性与胰岛素抵抗和2型糖尿病密切相关。GPR 40是一种G蛋白偶联受体，介导游离脂肪酸诱导的胰岛素分泌，因此在改善糖尿病方面发挥有益作用。然而，GPR 40激动剂对肝脂肪变性的影响仍有待阐明。在本研究中，我们发现GPR 40的激动剂GW 9508的激活减弱肝X受体（LXR）诱导的肝脏脂质蓄积。在喂食高胆固醇饮食的C57 BL/6小鼠的肝脏中以及在由化学激动剂刺激的HepG 2细胞中，LXR的激活导致其靶脂肪生成基因的表达增加以及随后的脂质积聚。在GW 9508补充后，LXR的所有这些作用均显著下调。此外，GPR 40的激活伴随着AMPK通路的上调，而GPR 40对脂肪生成基因表达的抑制作用在很大程度上被AMPK敲低所消除。综上所述，我们的结果表明，GW 9508通过调节AMPK信号通路发挥有益作用，以改善LXR诱导的肝脂肪变性。
Hepatic steatosis is strongly linked to insulin resistance and type 2 diabetes. GPR40 is a G protein-coupled receptor mediating free fatty acid-induced insulin secretion and thus plays a beneficial role in the improvement of diabetes. However, the impact of GPR40 agonist on hepatic steatosis still remains to be elucidated. In the present study, we found that activation of GPR40 by its agonist GW9508 attenuated Liver X receptor (LXR)-induced hepatic lipid accumulation. Activation of LXR in the livers of C57BL/6 mice fed a high-cholesterol diet and in HepG2 cells stimulated by chemical agonist caused increased expression of its target lipogenic genes and subsequent lipid accumulation. All these effects of LXR were dramatically downregulated after GW9508 supplementation. Moreover, GPR40 activation was accompanied by upregulation of AMPK pathway, whereas the inhibitive effect of GPR40 on the lipogenic gene expression was largely abrogated by AMPK knockdown. Taken together, our results demonstrated that GW9508 exerts a beneficial effect to ameliorate LXR-induced hepatic steatosis through regulation of AMPK signaling pathway.