Human islet amyloid polypeptide aggregation upregulates the mitochondrial cholesterol transport protein StAR and induces mitochondrial dysfunction in beta cells.

aims/hypothesisLoss of islet beta cell function and mass are critical in the pathogenesis of type 2 diabetes, a disease in which ~90% of individuals exhibit islet amyloid deposition. Amyloid deposits comprise the normal beta cell secretory product, human islet amyloid polypeptide (hIAPP), the aggregation of which is toxic to beta cells. While the underlying mechanism(s) for toxicity remain unknown, it is likely to involve mitochondrial dysfunction. We have shown that the mitochondrial cholesterol transport protein, steroidogenic acute regulatory protein (StAR), is upregulated in beta cells following amyloid deposition. Here, we examined the role of StAR in the toxicity of islet amyloidosis.

methodsHuman islets from non-diabetic donors were cultured under amyloidogenic conditions and StAR expression was examined. StAR expression was also determined in islets isolated from transgenic mice expressing amyloidogenic hIAPP or non-transgenic littermates expressing non-amyloidogenic islet amyloid polypeptide, cultured under amyloidogenic conditions with or without the addition of an amyloid inhibitor. Total islet cholesterol content, mitochondrial cholesterol content, mitochondrial function and cell viability/death were compared in transgenic hIAPP and non-transgenic islets cultured in amyloidogenic conditions. Additionally, StAR localisation to islet cells, as well as its intracellular localisation, was examined.

resultsStAR was present in human islets at the mRNA and protein level, and expression increased significantly with amyloid formation in vitro. Further, in hIAPP transgenic mouse islets, StAR expression was amyloid-dependent. StAR was predominantly expressed in beta cells, and the amyloid-induced increase in StAR protein was found specifically in the mitochondrial fraction. While total and mitochondrial cholesterol content was unchanged between non-transgenic and hIAPP transgenic mouse islets cultured under amyloidogenic conditions, increased StAR expression was associated with decreased mitochondrial glucose-stimulated respiration and increased cell death. CONCLUSIONS/

interpretationThese findings are consistent with StAR having a pathophysiological role in the beta cell in type 2 diabetes, where its upregulation under conditions of islet amyloid deposition could contribute to mitochondrial dysfunction.