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Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation

BACKGROUND: Emerging 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 produc...

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Autores principales: Hong, Seok-Woo, Lee, Jinmi, Kwon, Hyemi, Park, Se Eun, Rhee, Eun-Jung, Park, Cheol-Young, Oh, Ki-Won, Park, Sung-Woo, Lee, Won-Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Endocrine Society 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145960/
https://www.ncbi.nlm.nih.gov/pubmed/30229580
http://dx.doi.org/10.3803/EnM.2018.33.3.403
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author Hong, Seok-Woo
Lee, Jinmi
Kwon, Hyemi
Park, Se Eun
Rhee, Eun-Jung
Park, Cheol-Young
Oh, Ki-Won
Park, Sung-Woo
Lee, Won-Young
author_facet Hong, Seok-Woo
Lee, Jinmi
Kwon, Hyemi
Park, Se Eun
Rhee, Eun-Jung
Park, Cheol-Young
Oh, Ki-Won
Park, Sung-Woo
Lee, Won-Young
author_sort Hong, Seok-Woo
collection PubMed
description BACKGROUND: Emerging 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). METHODS: We 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. RESULTS: Lack 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. CONCLUSION: Altogether, 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.
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spelling pubmed-61459602018-09-25 Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation Hong, Seok-Woo Lee, Jinmi Kwon, Hyemi Park, Se Eun Rhee, Eun-Jung Park, Cheol-Young Oh, Ki-Won Park, Sung-Woo Lee, Won-Young Endocrinol Metab (Seoul) Original Article BACKGROUND: Emerging 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). METHODS: We 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. RESULTS: Lack 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. CONCLUSION: Altogether, 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. Korean Endocrine Society 2018-09 2018-09-18 /pmc/articles/PMC6145960/ /pubmed/30229580 http://dx.doi.org/10.3803/EnM.2018.33.3.403 Text en Copyright © 2018 Korean Endocrine Society http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Hong, Seok-Woo
Lee, Jinmi
Kwon, Hyemi
Park, Se Eun
Rhee, Eun-Jung
Park, Cheol-Young
Oh, Ki-Won
Park, Sung-Woo
Lee, Won-Young
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation
title 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_short 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
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145960/
https://www.ncbi.nlm.nih.gov/pubmed/30229580
http://dx.doi.org/10.3803/EnM.2018.33.3.403
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