Paper published in a journal (Scientific congresses and symposiums)
Cholesterol Accumulation in Islets Increases Steroidogenic Acute Regulatory (StAR) Protein Expression and Decreases Islet Cell Viability and ß-Cell Function
1457-P: Cholesterol Accumulation in Islets Increases Steroidogenic Acute Regulatory (StAR) Protein Expression and Decreases Islet Cell Viability and ß-Cell Function | Diabetes | American Diabetes Association.pdf
Endocrinology, Diabetes and Metabolism; Internal Medicine
Abstract :
[en] Diabetes is associated with elevated plasma cholesterol (Chol) , with its intracellular accumulation resulting in β-cell dysfunction. In steroidogenic tissues, StAR facilitates Chol transport from the outer to inner mitochondrial membrane for subsequent metabolism. We have shown that StAR is expressed in β cells and its upregulation increases mitochondrial Chol content and decreases mitochondrial function. To determine whether excess Chol per se increases StAR expression and reduces islet viability, we cultured mouse islets for 24 hours in Chol and quantified mRNA levels of Star and genes involved in Chol synthesis (Hmgcr) , uptake (Ldlr) and efflux (Abca1) , cell viability and glucose stimulated insulin secretion (GSIS) . Islet Chol content increased with increasing Chol concentrations (27.1±1.7, 55.3±0.5 and 72.7±5.2 µg/mg protein for 0, 0.25 and 0.5 mM respectively; n=3, p<0.0by ANOVA) , with mitochondrial Chol increasing 2.4-fold in 0.5 mM (9.1±0.2 to 22.4±1.9 µg/mg protein; n=3, p<0.005) . This was associated with increased Star mRNA expression (1.0±0.1, 3.0±0.9 and 7.0±1.5; n=3, p=0.014) . Further, mRNA expression of Hmgcr tended to decrease (1.0±0.2, 0.8±0.3 and 0.3±0.0; n=3, p=0.088) , whereas expression of Ldlr and Abca1 did not change (Ldlr: 1.7±0.8, 1.1±0.7 and 0.5±0.3; n=3, p=0.508; Abca1: 1.1±0.3, 1.9±0.7 and 1.1±0.1; n=3, p=0.413) . These changes were associated with reductions in cell viability (100±15.7%, 68.0±12.6% and 57.3±9.6%; n=2, p=0.025) and GSIS in response to 20 mM glucose (fold increase over 2.8 mM: 0 mM Chol 28.5±0.6, 0.25 mM Chol 8.9±0.5, 0.5 mM Chol 10.8±0.9; n=2, p<0.0001) .
In summary, islet cholesterol accumulation is associated with increased StAR expression, decreased cell viability and reduced β-cell function. These data suggest that elevated cholesterol in diabetes may contribute to β-cell dysfunction by increasing StAR expression and mitochondrial cholesterol accumulation.
Disclosure
R.Akter: None. M.F.Hogan: Employee; NanoString. N.Esser: None. J.J.Castillo: None. R.L.Hull-meichle: Research Support; Casma Therapeutics. S.Zraika: None. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc.
Funding
VA (I01BX001060) ,VA (IBX004063) ,NIDDK (P30 DK017047) ,NIDDK (T32 DK007247)
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
AKTER, REHANA; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
HOGAN, MEGHAN F.; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
Esser, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques ; Université de Liège - ULiège > GIGA > GIGA I3 - Immunometabolism and Nutrition ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
CASTILLO, JOSEPH J.; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
HULL-MEICHLE, REBECCA L.; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
ZRAIKA, SAKENEH; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
KAHN, STEVEN E.; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
Language :
English
Title :
Cholesterol Accumulation in Islets Increases Steroidogenic Acute Regulatory (StAR) Protein Expression and Decreases Islet Cell Viability and ß-Cell Function
Publication date :
01 June 2022
Event name :
American Diabetes Association 82nd Scientific Sessions (ADA)
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