Chronic palmitate exposure inhibits AMPKa and decreases glucose-stimulated insulin secretion from β-cells： modulation by fenofibrate  

作　　者：Ying SUN Meng REN Guan-qi GAO Bendi GONG Wei XIN Hua GUO Xiu-juan ZHANG Ling GAO Jia-jun ZHAO 

机构地区：[1]Department of Endocrinology , Shandong University, Jinan 250021, China [2]Central Laboratory of Shandong Provincial Hospital, Shandong University, Jinan 250021, China [3]Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA [4]Department of Endocrinology, Linyi People's Hospital, Linyi 276003, China

出　　处：《Acta Pharmacologica Sinica》2008年第4期443-450,共8页中国药理学报（英文版）

基　　金：Project supported by a grant from National Natural Science Foundation of China （№ 30670994）.Acknowledgements The authors thank Professor Xiao HAN for providing us with the INS-1 cells, and also the teachers at the Science Center of Shandong Provincial Hospital （Jinan, China） for excellent technical assistance.

摘　　要：Aim： Adenosine monophosphate-activated protein kinase （AMPK）, a vital regulator of glucose metabolism, may affect insulin secretion in β-cells. However, the role of AMPK in β-cell lipotoxicity remains unclear. Fenofibrate has been reported to regulate lipid homeostasis and is involved in insulin secretion in pancreatic β-cells. In the present study, we aimed to investigate the effect of palmitate on AMPK expression and glucose-stimulated insulin secretion （GSIS） in rat islets and INS-1 β-cell, as well as the effect of fenofibrate on AMPK and GSIS in INS-1 cells treated with palmitate. Methods： Isolated rat islets and INS-1 β-cells were treated with and without palmitate or fenofibrate for 48 h. The mRNA levels of the AMPKα isoforms were measured by real-time PCR. Western blotting was used to detect the protein expression of total AMPKα （T- AMPKα）, phosphorylated AMPKα （P-AMPKα）, and phosphorylated acetyl coenzyme A carboxylase （P-ACC）. Insulin secretion was detected by radioimmunoassay induced by 20 mmol/L glucose as GSIS. Results： The results showed that chronic exposure of β-cells to palmitate for 48 h inhibited the expression of AMPKαO mRNA and T-AMPKα protein levels, as well as P-AMPKα and P- ACC protein expressions in a dose-dependent manner. Accordingly, GSIS was inhibited by palmitate. Compared with the palmitate-treated cells, fenofibrate ameliorated these changes impaired by palmitate and exhibited a significant el- evation in the expression of AMPKα and GSIS. Conclusion： Our findings suggest a role of AMPKα reduction in β-cell lipotoxicity and a novel role of fenofibrate in improving GSIS associated with the AMPKα activation in β-cells chronically exposed to palmitate.Aim： Adenosine monophosphate-activated protein kinase （AMPK）, a vital regulator of glucose metabolism, may affect insulin secretion in β-cells. However, the role of AMPK in β-cell lipotoxicity remains unclear. Fenofibrate has been reported to regulate lipid homeostasis and is involved in insulin secretion in pancreatic β-cells. In the present study, we aimed to investigate the effect of palmitate on AMPK expression and glucose-stimulated insulin secretion （GSIS） in rat islets and INS-1 β-cell, as well as the effect of fenofibrate on AMPK and GSIS in INS-1 cells treated with palmitate. Methods： Isolated rat islets and INS-1 β-cells were treated with and without palmitate or fenofibrate for 48 h. The mRNA levels of the AMPKα isoforms were measured by real-time PCR. Western blotting was used to detect the protein expression of total AMPKα （T- AMPKα）, phosphorylated AMPKα （P-AMPKα）, and phosphorylated acetyl coenzyme A carboxylase （P-ACC）. Insulin secretion was detected by radioimmunoassay induced by 20 mmol/L glucose as GSIS. Results： The results showed that chronic exposure of β-cells to palmitate for 48 h inhibited the expression of AMPKαO mRNA and T-AMPKα protein levels, as well as P-AMPKα and P- ACC protein expressions in a dose-dependent manner. Accordingly, GSIS was inhibited by palmitate. Compared with the palmitate-treated cells, fenofibrate ameliorated these changes impaired by palmitate and exhibited a significant el- evation in the expression of AMPKα and GSIS. Conclusion： Our findings suggest a role of AMPKα reduction in β-cell lipotoxicity and a novel role of fenofibrate in improving GSIS associated with the AMPKα activation in β-cells chronically exposed to palmitate.

关 键 词：adenosine monophosphate-activated protein kinase （AMPK） FENOFIBRATE PALMITATE   pancreatic β-cells acetyl coenzyme A carboxylase INS- 1 cells 

分 类 号：Q55[生物学—生物化学]