title: Distinct pathways of cholesterol biosynthesis impact on insulin secretion.
abstract: Results from previous investigations have indicated that glucose-stimulated insulin secretion (GSIS) is affected by changes in cholesterol and its intermediates, but the precise link between secretion and cholesterol has not been thoroughly investigated. In this study, we show the contribution of both protein isoprenylation and cholesterol-dependent plasma membrane structural integrity to insulin secretion in INS-1E cells and mouse islets. Acute (2 h) inhibition of hydroxyl-methylglutaryl-CoA reductase by simvastatin (SIM) resulted in inhibition of GSIS without reduction in total cellular cholesterol content. This effect was prevented by cell loading with the isoprenyl molecule geranylgeranyl pyrophosphate. Chronic (24 h) inhibition of cholesterol biosynthesis resulted in inhibition of GSIS with a significant reduction in total cellular cholesterol content, which was also observed after the inhibition of cholesterol biosynthesis downstream of isoprenoid formation. Electron paramagnetic resonance analyses of INS-1E cells showed that the SIM-induced reduction in cholesterol increased plasma membrane fluidity. Thus, the blockade of cholesterol biosynthesis resulted in the reduction of availability of isoprenoids, followed by a reduction in the total cholesterol content associated with an increase in plasma membrane fluidity. Herein, we show the different contributions of cholesterol biosynthesis to GSIS, and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper β-cell function.
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt jpzuniga@icb.usp.br.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Zúñiga-Hertz
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rebelato
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt.
authors.forename: Adam
authors.initials: A
authors.lastname: Kassan
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt.
authors.forename: Abdelrahman M
authors.initials: AM
authors.lastname: Khalifa
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt.
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: Department of Physiology and BiophysicsInstitute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, 05508-000 São Paulo, BrazilDepartment of AnesthesiologyVA San Diego Healthcare System and University of California-San Diego, VASDHS (9125), 3350 La Jolla Village Drive, San Diego, California 92161, USAHelmy Institute for Medical SciencesCenter for Aging and Associated Diseases, Zewail City of Sciences and Technology, Giza, Egypt.
authors.forename: Fernando
authors.initials: F
authors.lastname: Abdulkader
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008560:Membrane Fluidity / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D051379:Mice; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D014233:Tricarboxylic Acids / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007328:Insulin; D011106:Polyisoprenyl Phosphates; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D002784:Cholesterol; D019821:Simvastatin; D005947:Glucose; C002963:geranylgeranyl pyrophosphate
keywords: cholesterol; isoprenylation; membrane; secretion