Pathogenesis and Impact of Islet Amyloid

项目总结

Project Summary Abnormal cholesterol metabolism is associated with cardiovascular disease, the leading cause of death in diabetes. The pathological hallmark of the hyperglycemia of diabetes is β-cell dysfunction and loss. Increased intracellular cholesterol accumulation leads to β-cell dysfunction and loss; thus, preventing the deleterious effects of cholesterol on the β-cell is important for attaining glycemic control in diabetes. The mechanism by which excess cholesterol induces β-cell dysfunction/death has not been completely elucidated. The mitochondrial membrane protein, Steroidogenic Acute Regulatory Protein (StAR), facilitates cholesterol transport from the outer to inner mitochondrial membrane. In steroidogenic tissues, StAR-mediated cholesterol transport is a critical regulatory step in steroidogenesis. Once transported into mitochondria by StAR, cholesterol is metabolized by the mitochondrial cytochrome P450 (CYP) family enzymes into steroid hormones, bile acids or oxysterols. The production of oxysterols, which are critical regulators of cholesterol homeostasis, is dependent on the enzyme sterol-27-hydroxylase (CYP27A1). We have found StAR to be present in β-cells, to be upregulated under diabetogenic conditions, and when overexpressed in β-cells results in increased mitochondrial cholesterol accumulation, mitochondrial dysfunction and loss of cell viability. My preliminary data shows that increased exogenous cholesterol per se upregulates StAR in islets resulting in increased mitochondrial cholesterol and these same functional abnormalities. Further, my preliminary data show that while CYP27A1 and the cholesterol efflux regulatory protein, ATP-binding cassette transporter (ABCA1), are expressed in islets, neither of them increase as a compensatory response to increased cholesterol accumulation. Therefore, in this proposal, I will address the hypothesis that increased cholesterol accumulation in β-cells results in StAR-mediated mitochondrial cholesterol accumulation, mitochondrial dysfunction, and β-cell dysfunction. In Specific Aim 1, I will investigate whether StAR mediates cholesterol- induced β-cell dysfunction and loss. Islets from the β-cell specific StAR deficient mice will be used to determine whether StAR deficiency can reduce cholesterol-induced mitochondrial dysfunction, β-cell dysfunction and loss. In Specific Aim 1, I will also determine whether overexpression of CYP27A1 can rescue islets from cholesterol-induced, StAR-mediated mitochondrial dysfunction, thereby improving β-cell function. In Specific Aim 2, I will investigate whether β-cell-specific knockout of StAR improves insulin secretory dysfunction, glucose tolerance and reduces β-cell loss in hypercholesterolemic mice. These studies will provide new insights into cholesterol-induced β-cell dysfunction and broaden our knowledge of the role of StAR in islet cholesterol metabolism and mitochondrial function. Thereby, they will elucidate whether StAR may be a novel therapeutic target for the preservation of β-cells in diabetes. This fellowship will be done at VA Puget Sound Health Care System and the University of Washington using the multiple resources of these two institutions coupled with their strong postdoctoral and early career training programs in diabetes, obesity and metabolism. The ultimate goal is to provide the necessary tolls and data to apply for a career development award and launch my career as an independent scientist working on diabetes, a disease that is very common in Veterans.