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Increased Steroidogenic Acute Regulatory Protein Contributes to Cholesterol-induced β-Cell Dysfunction
Rehana Akter1, Meghan F Hogan1, Nathalie Esser1,2
1Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Endocrinology
|February 10, 2025
Summary
High cholesterol in type 2 diabetes impairs insulin secretion. Steroidogenic acute regulatory protein (StAR) increases mitochondrial cholesterol, leading to islet beta-cell dysfunction and reduced insulin release.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolic Diseases
Background:
- Hypercholesterolemia is common in type 2 diabetes.
- Cholesterol buildup in islet beta-cells causes insulin secretory dysfunction, a hallmark of diabetes.
- Steroidogenic acute regulatory protein (StAR) expression increases in islets during beta-cell dysfunction.
Purpose of the Study:
- To investigate the role of StAR in mitochondrial cholesterol accumulation.
- To determine StAR's contribution to cholesterol-induced beta-cell dysfunction in type 2 diabetes.
Main Methods:
- Isolated mouse islets were treated with excess cholesterol.
- StAR expression was analyzed.
- Mitochondrial cholesterol content, membrane potential, and oxidative phosphorylation were measured.
- INS-1 cells were engineered to overexpress StAR using lentivirus.
Main Results:
- Cholesterol treatment upregulated StAR expression in islets.
- This led to mitochondrial cholesterol accumulation, reduced mitochondrial membrane potential, and impaired oxidative phosphorylation.
- Insulin secretion and islet insulin content were decreased.
- StAR overexpression in INS-1 cells mimicked these effects.
Conclusions:
- Elevated cholesterol in diabetes may cause beta-cell dysfunction.
- StAR-mediated mitochondrial cholesterol transport and accumulation are implicated in this process.
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