Regulation of hormone-sensitive lipase in islets

Abstract 

An unique isoform of hormone-sensitive lipase (HSL) is expressed in β-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 β-cell HSL and increased HSL hydrolytic activity in clonal β-cells. Short-term treatment with GLP-1 increased HSL activity without changing the expression of the β-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 β-cell isoform of HSL is involved in maintaining lipid homeostasis in islets and contributes to the proper control of GSIS.

Abbreviations: HSL, hormone-sensitive lipase, TG, triglyceride, CE, cholesteryl ester, FFA, free fatty acid, NC, normal chow, HF, high fat, ACRP30, adipocyte complement-related protein of 30kDa, PPAR, peroxisome proliferator-activated receptor, C/EBP, CAAT/enhancer binding protein, SREBP, sterol regulatory element binding protein, LPL, lipoprotein lipase, GPAT, glycerol-3-phosphate acyltransferase, DGAT, acyl-CoA:diacylglycerol acyltransferase, FAS, fatty acid synthase, ACLY, ATP citrate lyase, ACAT, acyl-CoA:cholesterol acyltransferase, UCP, uncoupling protein, ACC-1, acyl-CoA carboxylase-1, SCD1, stearoyl-CoA desaturase 1, GPR40, G-protein-coupled cell-surface receptor, GLP-1, glucagon-like peptide-1

Keywords: Hormone-sensitive lipase, Glucose stimulated insulin secretion, Lipid homeostasis