Peyot Marie-Line, Nolan Christopher J, Soni Krishnakant, Joly Erik, Lussier Roxane, Corkey Barbara E, Wang Shu Pei, Mitchell Grant A, Prentki Marc
Molecular Nutrition Unit, Department of Nutrition, University of Montréal and the Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Diabetes. 2004 Jul;53(7):1733-42. doi: 10.2337/diabetes.53.7.1733.
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 beta-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 beta-cell signaling for secretion in response to glucose.
我们之前报道过，在体内和体外实验中，激素敏感脂肪酶基因敲除小鼠（HSL(-/-)）的葡萄糖刺激胰岛素分泌（GSIS）均有所下降。当前研究的重点是进一步深入了解胰岛组织中脂解作用的信号传导作用及调控机制。我们还研究了胰高血糖素样肽1（GLP-1）对GSIS的影响，因为GLP-1可通过蛋白激酶A激活HSL和脂解作用来增强GSIS。对4个月和7个月大的禁食及喂食状态下的雄性HSL(-/-)和野生型（HSL(+/+)）小鼠新鲜分离的胰岛进行了研究。4个月和7个月大的雄性HSL(-/-)小鼠胰岛中的中性胆固醇酯水解酶活性均显著降低，而甘油三酯脂肪酶活性的显著缺陷仅在年龄较大的小鼠中才明显。脂肪酶活性的缺陷与胰岛甘油三酯含量升高以及基础葡萄糖水平下脂解作用降低有关。野生型和HSL基因敲除小鼠的胰岛中，高葡萄糖均可刺激脂解作用。我们发现严重的GSIS缺陷，但仅存在于7个月大、禁食的雄性HSL(-/-)小鼠的胰岛中。4个月大的禁食雄性HSL(-/-)小鼠的GSIS受影响较小，雌性小鼠中则未降低。外源性递送游离脂肪酸（FFA）可挽救GSIS，这支持了一种观点，即HSL(-/-)小鼠中缺乏用于脂质信号传导过程的内源性FFA供应是导致GSIS丧失的原因。GLP-1也可挽救HSL(-/-)小鼠的GSIS，表明通过HSL的信号传导不是其肠促胰岛素效应的主要途径。因此，HSL基因敲除小鼠的分泌表型具有性别依赖性，随年龄增加，且受营养状态影响。在大多数情况下，β细胞中脂解通量的主要决定因素涉及一种或多种除HSL之外的酶，这些酶可被葡萄糖急性激活。我们的结果支持这样一种观点，即通过HSL和其他一种或多种酶提供的内源性FFA可参与为β细胞信号传导提供脂质部分，以响应葡萄糖进行分泌。
