Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion
Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion
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DOI：
10.1074/jbc.m109.006650
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发表时间：
2009-06-19
影响因子：
4.8
通讯作者：
Prentki, Marc
中科院分区：
文献类型：
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作者：
Peyot, Marie-Line;Guay, Claudiane;Prentki, Marc
在对葡萄糖敏感的脂肪酶缺陷小鼠中减少的脂肪分解与受损的葡萄糖刺激的胰岛素分泌（GSIS）相关，表明内源性β细胞脂质储存为胰岛素释放提供信号分子。来自HSL-/-小鼠的胰岛中的脂解和甘油三酯（TG）脂肪酶活性的测量表明β细胞中存在其他TG脂肪酶。采用真实的时间定量PCR方法，发现脂肪甘油三酯脂肪酶（ATGL）是大鼠胰岛和INS 832/13细胞中最丰富的TG脂肪酶。为了评估其在胰岛素分泌中的作用，通过小发夹RNA降低INS 832/13细胞中的ATGL表达（ATGL敲低（KD））。ATGL-KD促进游离脂肪酸（FFA）酯化为TG。ATGL-KD细胞显示葡萄糖或Gln + Leu诱导的胰岛素释放减少，以及在高血糖下对KCl或棕榈酸盐的反应减少，但在低血糖下则没有。GSIS的K-ATP非依赖性/扩增途径在ATGL-KD细胞中显著减少。ATGL（-/-）小鼠出现低胰岛素血症和低血糖，并显示血浆TG和FFA降低。高血糖钳夹显示ATGL（-/-）小鼠的胰岛素敏感性增加，GSIS和精氨酸诱导的胰岛素分泌减少。因此，从ATGL（-/-）小鼠分离的胰岛显示响应于葡萄糖、葡萄糖+棕榈酸盐和KCl的胰岛素分泌减少。在ATGL（-/-）胰岛中，胰岛TG含量和FFA酯化为TG增加了2倍，但葡萄糖的利用和氧化没有改变。结果表明ATGL和细胞内脂质信号传导对于燃料和非燃料诱导的胰岛素分泌的重要性。
Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous beta-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL-/- mice indicated the presence of other TG lipase(s) in the beta-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13cells(ATGL-knock-down (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucose- or Gln + Leu-induced insulin release, as well as reduced response to KCl or palmitate at high, but not low, glucose. The K-ATP-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL(-/-) mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL(-/-) mice. Accordingly, isolated islets from ATGL(-/-) mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCl. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL(-/-) islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fuel-and nonfuel-induced insulin secretion.