Li Meng, Meng Xiangyu, Xu Jie, Huang Xiuqing, Li Hongxia, Li Guoping, Wang Shu, Man Yong, Tang Weiqing, Li Jian
Peking University Fifth School of Clinical Medicine (Beijing Hospital), Beijing, China.
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Sci Rep. 2016 Apr 28;6:25237. doi: 10.1038/srep25237.
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.
肝脂肪变性与胰岛素抵抗和2型糖尿病密切相关。GPR40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，GPR40激动剂对肝脂肪变性的影响仍有待阐明。在本研究中，我们发现其激动剂GW9508激活GPR40可减轻肝脏X受体（LXR）诱导的肝脏脂质积累。在喂食高胆固醇饮食的C57BL/6小鼠肝脏中以及在化学激动剂刺激的HepG2细胞中，LXR的激活导致其靶标生脂基因表达增加以及随后的脂质积累。补充GW9508后，LXR的所有这些作用均显著下调。此外，GPR40激活伴随着AMPK途径的上调，而AMPK敲低在很大程度上消除了GPR40对生脂基因表达的抑制作用。综上所述，我们的结果表明，GW9508通过调节AMPK信号通路对改善LXR诱导的肝脂肪变性发挥有益作用。
