Hormone-Sensitive Lipase and the Pancreatic Beta-Cell

Sammanfattning: Hormone-sensitive lipase (HSL) is a key enzyme in fatty acid mobilization. It is acutely regulated by extracellular signals via reversible phosphorylation. In the recent past, the focus of type 2 diabetes research has moved towards the lipid component. Lipids interfere with glucose homeostasis in a multitude of ways; they can decrease insulin sensitivity of tissues and cause ?-cell dysfunction. Conversely, lipids are necessary for normal ?-cell function and can potentiate insulin secretion. This thesis pertains to the structure and function of HSL in ?-cells, as an intracellular lipase could well have a role in normal and perturbed ?-cell function. We have shown that HSL is present and active in ?-cells, as a novel isozyme, slightly larger than the predominant adipocyte HSL isoform. The larger size is due the inclusion of a 5’ coding exon in the HSL transcript (exon A). HSL is clustered in close association with the secretory granules within the ?-cell. Furthermore, the expression of HSL is induced in ?-cells when the ambient glucose concentration is elevated, as shown at transcript, protein, and activity levels. This effect is, at least partly, transcriptional and cis-acting, glucose-sensing capability has been demonstrated in sequence of the human HSL gene upstream of exon A. Investigation of transgenic mouse lines overexpressing HSL in ?-cells has revealed a role for HSL in lipotoxicity, as these mice develop an insulin deficiency when challenged with a high-fat diet. Concurrently, uncoupling protein 2 is upregulated in islets of these mice, possibly causing the observed secretory defect by lowering the metabolic efficacy in the ?-cells. In summary, this thesis has added to the knowledge about ?-cell lipid metabolism and specifically about the structure, function and regulation of HSL in these cells.