The Protective Effects of FGF21 on Lipotoxicity-induced Pancreatic Islet Dysfunction
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摘要A chronic exposure to high plasma levels of free fatty acids (FA) causes lipid accumulation within pancreatic islet β-cells, a process called lipotoxicity, that finally leads to islet dysfunction and β-cell demise in obesity-associated type 2 diabetes mellitus (T2DM). Fibroblast growth factor 21 (FGF21), a potent regulator of FA metabolism in the liver, has been shown to be positive for ameliorating islet function and proliferation. Despite this, the mechanism whereby FGF21 regulates islet FA metabolism and protects islet from lipotoxicity remains elusive. We thus aimed to prove that FGF21 can improve islet lipid metabolism by increasing the FA oxidation while reducing the lipid accumulation. To achieve this, rat β-cell line INS-1E, isolated mouse islets and transgenic mice with FGF21 and β-klotho (a specific cofactor of FGF21) knockout (KO) were used as in vitro, ex vivo and in vivo models, respectively, to study the effects of FGF21 on FA metabolism under normal and lipotoxic conditions. Preliminary results showed that exogenous administration of FGF21 in isolated islets increased the gene expression of carnitine palmitoyltransferase-1 (CPT1, a rate-limiting enzyme for FA oxidation) and acyl-CoA oxidase (ACO, an enzyme for β-oxidation). Meanwhile, FGF21 alleviated the palmitic acid-induced triglyceride accumulation via phosphorylation of acetyl-CoA carboxylase (ACC, an enzyme for FA synthesis), as well as reducing the expression of SREBP1c and FAS (factors for lipogenesis) in INS-1E cells. In addition, FGF21 reversed palmitic acid-induced islet oxidative stress and inflammation-related gene expression, such as iNOS, COX2 and IL1-β in isolated islets. Interestingly, decreases in gene expression of FA oxidation and glucose-stimulated insulin secretion with distorted islet α/β cell distribution were also observed in islets isolated from FGF21-KO mice. These data indicate that FGF21 would be protective against lipotoxicity-induced islet dysfunction in obesity-related T2DM.
著者Ting XIE, Wing Yan SO, Tsz Wai CHENG, Ai Min XU, Po Sing LEUNG
會議名稱76th Scientific Sessions | American Diabetes Association
會議開始日10.06.2016
會議完結日14.06.2016
會議地點New Orleans
會議國家/地區美國
出版年份2016
月份6
語言美式英語

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