Changes in cellular cholesterol levels may contribute to beta cell dysfunction. Islets from LDL receptor knockout mice (LDLR-/-) possess higher cholesterol content, showing impaired calcium handling and lower insulin secretion than wild type (WT) mice. The endogenous cholesterol synthesis occurs through a series of enzymatic reactions known as the Mevalonate pathway. When activated, this pathway generates intermediary that promote post-translational modifications in small Rho-GTPases proteins, through prenylation process. In beta cells, the Rho-GTPases promote actin cytoskeleton remodeling and are involved in the extrusion of insulin containing granules. Synthesis and accumulation of cholesterol in the endoplasmic reticulum (ER) are associated with the development of ER stress, resulting in a reduction of beta cell mass and function. Based on this, the aim of this project is to evaluate whether alterations in intracellular cholesterol metabolism leads to changes in localization, expression and activity of proteins that promote cytoskeletal rearrangement and extrusion of insulin granules, in islets from LDLR-/ - mice and MIN6 cells. In addition, we will analyze if the excess of cholesterol affects the expression of genes and protein markers of endoplasmic reticulum stress.
News published in Agência FAPESP Newsletter about the scholarship: