[en] Hypercholesterolemia is often observed in individuals with type 2 diabetes. Cholesterol accumulation in subcellular compartments within islet β-cells can result in insulin secretory dysfunction, which is a key pathological feature of diabetes. Previously, we demonstrated that expression of the mitochondrial cholesterol transport protein, steroidogenic acute regulatory protein (StAR), is induced in islets under conditions of β-cell dysfunction. However, whether it contributes to mitochondrial cholesterol accumulation in β-cells and cholesterol-induced β-cell dysfunction has not been determined. Thus, we sought to examine the role of StAR in isolated mouse islets under conditions of excess exogenous cholesterol. Cholesterol treatment of islets upregulated StAR expression, which was associated with cholesterol accumulation in mitochondria, decreased mitochondrial membrane potential and impaired mitochondrial oxidative phosphorylation. Impaired insulin secretion and reduced islet insulin content were also observed in cholesterol-laden islets. To determine the impact of StAR overexpression in β-cells per se, a lentivirus was used to increase StAR expression in INS-1 cells. Under these conditions, StAR overexpression was sufficient to increase mitochondrial cholesterol content, impair mitochondrial oxidative phosphorylation, and reduce insulin secretion. These findings suggest that elevated cholesterol in diabetes may contribute to β-cell dysfunction via increases in StAR-mediated mitochondrial cholesterol transport and accumulation.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Akter, Rehana ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Hogan, Meghan F ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Esser, Nathalie ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladies métaboliques ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Barrow, Breanne M ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Castillo, Joseph J ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Boyko, Edward J ; Epidemiologic Research and Information Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Templin, Andrew T ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA ; Department of Medicine, Roudebush Veterans Affairs Medical Center and Indiana University School of Medicine, Indianapolis, IN 46202, USA
Hull, Rebecca L ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Zraika, Sakeneh ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Kahn, Steven E ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Language :
English
Title :
Increased Steroidogenic Acute Regulatory Protein Contributes to Cholesterol-induced β-Cell Dysfunction.
United States Department of Veterans Affairs NIH - National Institutes of Health SFD - French Society of Diabetes UW - University of Washington
Funding text :
This work was supported by the Department of Veterans Affairs, VA Puget Sound Health Care System (Seattle, WA), Merit Review I01 BX001060 from the Department of Veterans Affairs (S.E.K.), National Institutes of Health (NIH) grant R01 DK134502 (S.Z.), Merit Review I01-BX004063 from the Department of Veterans Affairs (R.L.H.), and the Seattle Institute for Biomedical and Clinical Research. Salary support was provided by National Institutes of Health (NIH) grant T32 DK007247 (R.A., M.F.H., and A.T.T.), a DEI Research Supplement Award to VA Merit Review I01 BX001060 (R.A.), Dick and Julia McAbee Endowed Fellowship in Diabetes Research from the University of Washington (M.F.H. and N.E.), an American Diabetes Association Fellowship Award 1-18-PDF (M.F.H.), Belgian American Educational Foundation Postdoctoral Fellowship and French Society of Diabetes Young Francophone Researcher Postdoctoral Fellowship (N.E.), and T32 HL007028 (J.J.C.). In addition, the University of Washington Diabetes Research Center, funded by NIH grant P30 DK017047, provided support through the Metabolic and Cellular Phenotyping Core.
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