Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation
BackgroundEmerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product...
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doaj-985086c6c8c04ba984c71e683b6896982020-11-25T02:21:55ZengAcademya Publishing Co.Endocrinology and Metabolism2093-596X2093-59782018-09-0133340341210.3803/EnM.2018.33.3.403Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial DysregulationSeok-Woo Hong0Jinmi Lee1Hyemi Kwon2Se Eun Park3Eun-Jung Rhee4Cheol-Young Park5Ki-Won Oh6Sung-Woo Park7Won-Young Lee8Institute of Medical Research, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaInstitute of Medical Research, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, .KoreaBackgroundEmerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB).MethodsWe examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels.ResultsLack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends.ConclusionAltogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.https://e-enm.org/Synapse/Data/PDFData/2008ENM/enm-33-403.pdfSphingosine 1-phosphateSphingosine kinaseInsulin-secreting cellsMitochondriaProhibitin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Seok-Woo Hong Jinmi Lee Hyemi Kwon Se Eun Park Eun-Jung Rhee Cheol-Young Park Ki-Won Oh Sung-Woo Park Won-Young Lee |
spellingShingle |
Seok-Woo Hong Jinmi Lee Hyemi Kwon Se Eun Park Eun-Jung Rhee Cheol-Young Park Ki-Won Oh Sung-Woo Park Won-Young Lee Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation Endocrinology and Metabolism Sphingosine 1-phosphate Sphingosine kinase Insulin-secreting cells Mitochondria Prohibitin |
author_facet |
Seok-Woo Hong Jinmi Lee Hyemi Kwon Se Eun Park Eun-Jung Rhee Cheol-Young Park Ki-Won Oh Sung-Woo Park Won-Young Lee |
author_sort |
Seok-Woo Hong |
title |
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation |
title_short |
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation |
title_full |
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation |
title_fullStr |
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation |
title_full_unstemmed |
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation |
title_sort |
deficiency of sphingosine-1-phosphate reduces the expression of prohibitin and causes β-cell impairment via mitochondrial dysregulation |
publisher |
Academya Publishing Co. |
series |
Endocrinology and Metabolism |
issn |
2093-596X 2093-5978 |
publishDate |
2018-09-01 |
description |
BackgroundEmerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB).MethodsWe examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels.ResultsLack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends.ConclusionAltogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression. |
topic |
Sphingosine 1-phosphate Sphingosine kinase Insulin-secreting cells Mitochondria Prohibitin |
url |
https://e-enm.org/Synapse/Data/PDFData/2008ENM/enm-33-403.pdf |
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