Effects of Cholesterol in Pancreatic Islets - PROJECT SUMMARY/ABSTRACT Statins are the most commonly used cholesterol-lowering medication; however, statins increase the risk of new-onset type 2 diabetes (T2D). While this increased risk includes a direct effect of statins to impair islet β- cell function, the underlying mechanisms remain unclear. With statin use trending up among U.S. adults, there is an urgent need to better understand how statins lead to demise of the β cell – this knowledge will inform strategies aimed at reducing progression to T2D in patients on statin therapy. To this end, we have generated data that show a previously unrecognized effect of statins to promote mitochondrial cholesterol accumulation within islets. Surprisingly, there is almost no literature on mechanisms regulating mitochondrial cholesterol content in β cells. This knowledge gap will be addressed in the proposed studies, which focus on the role of cholesterol transport to mitochondria and its subsequent metabolism in statin-induced β-cell toxicity. Mitochondria are cholesterol-poor organelles, and thus are highly sensitive to even small increases in cholesterol content. Steroidogenic acute regulatory protein (StAR) and the closely related STARD3 protein mediate cholesterol transport to mitochondria. We show that both StAR and STARD3 are upregulated in statin- treated islets. In β cells, StAR overexpression results in mitochondrial cholesterol accumulation, impaired insulin release and reduced cell viability. Also, our data suggest β cells have limited capacity to metabolize cholesterol since they express only two of the cytochrome P450 enzymes known to initiate cholesterol metabolism. Of these, only CYP27A1 is downregulated in islets exposed to statins, and this is accompanied by an increase in miRNA-204, which can suppress CYP27A1 mRNA. We find that lack of islet CYP27A1 per se promotes mitochondrial cholesterol accumulation and impaired insulin secretion. Also, we show stimulating mitophagy to clear cholesterol-laden mitochondria in statin-treated islets protects against β-cell dysfunction. Based on our data, we hypothesize that statin-induced aberrations in cholesterol transport and metabolism lead to mitochondrial cholesterol accumulation, mitochondrial dysfunction, impaired insulin release and β-cell death. The following specific aims will address our hypothesis: Aim 1: To determine the contributions of transport of cholesterol to mitochondria, its subsequent metabolism, or clearance of cholesterol-laden mitochondria to statin-induced β-cell dysfunction/death. Aim 2: To determine whether reducing StAR and/or increasing CYP27A1 expression ameliorates the detrimental effects of statins on β-cell function and mass in vivo. Aim 3: To identify miRs that mitigate statin-induced dysregulation of cholesterol transport and metabolism genes in human islets. This research is innovative and significant, as investigating mitochondrial cholesterol accumulation and miRNAs in statin-induced β-cell dysfunction/death will inform strategies to mitigate the risk of developing T2D.
