Hormone-sensitive lipase has a role in lipid signaling for insulin secretion but is nonessential for the incretin action of glucagon-like peptide 1
Hormone-sensitive lipase has a role in lipid signaling for insulin secretion but is nonessential for the incretin action of glucagon-like peptide 1
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DOI：
10.2337/diabetes.53.7.1733
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发表时间：
2004-07-01
期刊：
影响因子：
7.7
通讯作者：
Prentki, M
中科院分区：
文献类型：
--
作者：
Peyot, ML;Nolan, CJ;Prentki, M
我们之前在体内和体外都报道了激素敏感脂肪酶缺失小鼠(HSL-/-)葡萄糖刺激的胰岛素分泌(GSIS)减少。目前研究的重点是进一步深入了解胰岛组织中脂解的信号作用和调节。研究了GLP-1对GSIS的影响，因为GLP-1可通过蛋白激酶A激活HSL和脂解而增强GSIS。对4、7个月龄禁食喂养的雄性HSL-/-和野生型(HSL+/+)小鼠新鲜分离的胰岛进行了研究。在4个月和7个月大的雄性HSL-/-小鼠的胰岛中，中性胆固醇酯水解酶活性显著降低，而甘油三酯脂肪酶活性的显著不足仅在老年小鼠中变得明显。脂肪酶活性的不足与胰岛甘油三酯含量较高和基础葡萄糖水平下脂肪分解减少有关。高糖刺激了野生型和HSL缺失型小鼠胰岛的脂解作用。在GSIS中发现了严重的缺陷，但仅在7月龄禁食的雄性HSL-/-小鼠的胰岛中。GSIS在4个月龄禁食的雄性HSL-/-小鼠中受影响较小，在雌性小鼠中不受影响。外源性游离脂肪酸(FFA)的传递挽救了GSIS，支持了内源性FFA缺乏对HSL-/-小鼠脂质信号过程的供应是GSIS丢失的原因的观点。GLP-1还挽救了HSL-/-小鼠的GSIS，表明通过HSL的信号不是其胰岛素效应的主要途径。因此，HSL缺失小鼠的分泌表型是性别相关的，随着年龄的增长而增加，并受到营养状态的影响。在大多数情况下，P细胞中脂解流量的主要决定因素涉及一种酶(S)，而不是HSL，该酶可被葡萄糖剧烈激活。我们的结果支持这样的观点，即通过HSL和一个额外的酶(S)获得内源FFA参与了为P细胞提供脂质部分以响应葡萄糖的分泌信号。
We previously reported decreased glucose-stimulated insulin secretion (GSIS) in hormone-sensitive lipase-null mice (HSL-/-), both in vivo and in vitro. The focus of the current study was to gain further insight into the signaling role and regulation of lipolysis in islet tissue. The effect of glucagon-like peptide 1 (GLP-1) on GSIS was also studied, as GLP-1 could augment GSIS via protein kinase A activation of HSL and lipolysis. Freshly isolated islets from fasted and fed male HSL-/- and wild-type (HSL+/+) mice were studied at ages 4 and 7 months. Neutral cholesteryl ester hydrolase activity was markedly reduced in islets from both 4-and 7-month-old male HSL-/- mice, whereas a marked deficiency in triglyceride lipase activity became evident only in the older mice. The deficiencies in lipase activities were associated with higher islet triglyceride content and reduced lipolysis at basal glucose levels. Lipolysis was stimulated by high glucose in islets of both wild-type and HSL-null mice. Severe deficiencies in GSIS were found, but only in islets from 7-month-old, fasted, male HSL-/- mice. GSIS was less affected in 4-month-old fasted male HSL-/- mice and not reduced in female mice. Exogenous delivery of free fatty acids (FFAs) rescued GSIS, supporting the view that the lack of endogenous FFA supply for lipid-signaling processes in HSL-/- mice was responsible for the loss of GSIS. GLP-1 also rescued GSIS in HSL-/- mice, indicating that signaling via HSL is not a major pathway for its incretin effect. Thus, the secretory phenotype of HSL-null mice is gender dependent, increases with age, and is influenced by the nutritional state. Under most circumstances, the major determinant of lipolytic flux in the P-cell involves an enzyme(s) other than HSL that is acutely activated by glucose. Our results support the view that the availability of endogenous FFA through HSL and an additional enzyme(s) is involved in providing lipid moieties for P-cell signaling for secretion in response to glucose.