Shen Wen-Jun, Liang Yu, Wang Jenny, Harada Kenji, Patel Shailja, Michie Sara A, Osuga Jun-Ichi, Ishibashi Shun, Kraemer Fredric B
Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Diabetes Res Clin Pract. 2007 Jan;75(1):14-26. doi: 10.1016/j.diabres.2006.05.001. Epub 2006 Jun 9.
An unique isoform of hormone-sensitive lipase (HSL) is expressed in beta-cells. Recent findings suggest that HSL could be involved in the regulation of glucose stimulated insulin secretion (GSIS), however, these findings are controversial. To test the hypothesis that HSL is involved in control of normal GSIS via changes in its expression and/or activity in response to stimuli, we examined the effects of free fatty acid (FFA) loading and glucagon like peptide-1 (GLP-1) stimulation on the regulation of HSL expression and activity. With prolonged FFA loading, there was increased expression of beta-cell HSL and increased HSL hydrolytic activity in clonal beta-cells. Short-term treatment with GLP-1 increased HSL activity without changing the expression of the beta-cell isoform of HSL. Basal insulin secretion was increased, whereas GLP-1 potentiation of GSIS was decreased in islets isolated from HSL-/- mice, as compared to islets from wild type mice. Furthermore, using PancChip 2.2 cDNA microarrays (NIDDK consortium), the gene expression profile in the islets of HSL-/- mice was compared with wild type mice. Results showed changes in several metabolic pathways due to changes in lipid homeostasis caused by inactivation of HSL. Quantitative PCR for selected genes also revealed changes in genes that are related to insulin secretion, such as UCP-2. Therefore, these results suggest that the beta-cell isoform of HSL is involved in maintaining lipid homeostasis in islets and contributes to the proper control of GSIS.
一种独特的激素敏感性脂肪酶（HSL）同工型在β细胞中表达。最近的研究结果表明，HSL可能参与葡萄糖刺激的胰岛素分泌（GSIS）的调节，然而，这些结果存在争议。为了验证HSL通过响应刺激改变其表达和/或活性参与正常GSIS控制的假说，我们研究了游离脂肪酸（FFA）负荷和胰高血糖素样肽-1（GLP-1）刺激对HSL表达和活性调节的影响。随着FFA负荷时间延长，克隆β细胞中β细胞HSL的表达增加，HSL水解活性增强。GLP-1短期处理可增加HSL活性，而不改变β细胞HSL同工型的表达。与野生型小鼠分离的胰岛相比，从HSL-/-小鼠分离的胰岛中基础胰岛素分泌增加，而GLP-1对GSIS的增强作用降低。此外，使用PancChip 2.2 cDNA微阵列（NIDDK联盟），将HSL-/-小鼠胰岛中的基因表达谱与野生型小鼠进行比较。结果显示，由于HSL失活导致脂质稳态改变，几种代谢途径发生了变化。对选定基因的定量PCR也揭示了与胰岛素分泌相关的基因变化，如UCP-2。因此，这些结果表明，HSL的β细胞同工型参与维持胰岛中的脂质稳态，并有助于对GSIS进行适当控制。
