GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway.
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.
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.
Meng
M
Li
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.
Xiangyu
X
Meng
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Jie
J
Xu
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Xiuqing
X
Huang
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Hongxia
H
Li
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Guoping
G
Li
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Shu
S
Wang
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Yong
Y
Man
The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics &Beijing Hospital, Ministry of Health, Beijing, China.
Weiqing
W
Tang
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.
Jian
J
Li
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors / Q000378:metabolism*; D008744:Methylamines / Q000008:administration & dosage; D008810:Mice, Inbred C57BL; D011422:Propionates / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
C473036:Ffar1 protein, mouse; C515630:GW9508; D000071518:Liver X Receptors; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D055372:AMP-Activated Protein Kinases