Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.

Elevated extracellular free fatty acids (FFAs) can induce pancreatic beta cell apoptosis, thereby contributing to the pathogenesis of type 2 diabetes mellitus (T2D). Mitochondrial dysfunction has been implicated in FFA-induced beta cell apoptosis. However, molecular mechanisms linking mitochondrial...

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Autores principales:	Liang Peng, Xiuli Men, Wenjian Zhang, Haiyan Wang, Shiqing Xu, Qing Fang, Honglin Liu, Wenying Yang, Jinning Lou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd19bf199059401fa2d602abc0109dc0
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spelling	oai:doaj.org-article:cd19bf199059401fa2d602abc0109dc02021-11-18T08:08:46ZInvolvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.1932-620310.1371/journal.pone.0049258https://doaj.org/article/cd19bf199059401fa2d602abc0109dc02012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23166623/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Elevated extracellular free fatty acids (FFAs) can induce pancreatic beta cell apoptosis, thereby contributing to the pathogenesis of type 2 diabetes mellitus (T2D). Mitochondrial dysfunction has been implicated in FFA-induced beta cell apoptosis. However, molecular mechanisms linking mitochondrial dysfunction and FFA-induced beta cell apoptosis are not clear. Dynamin-related protein 1 (DRP-1) is a mitochondrial fission modulator. In this study, we investigated its role in FFA-induced INS-1 beta cell apoptosis. DRP-1 protein was promptly induced in INS-1 cells and rat islets after stimulation by FFAs, and this DRP-1 upregulation was accompanied by increased INS-1 cell apoptosis. Induction of DRP-1 expression significantly promoted FFA-induced apoptosis in DRP-1 WT (DRP-1 wild type) inducible INS-1-derived cell line, but not in DRP-1K38A (a dominant negative mutant of DRP-1) inducible INS-1-derived cell line. To validate these in vitro results, we transplanted DRP-1 WT or DRP-1 K38A cells into renal capsules of streptozotocin (STZ)-treated diabetic mice to study the apoptosis in xenografts. Consistent with the in vitro results, the over-expression of DRP-1 led to aggravated INS-1-derived cell apoptosis triggered by FFAs. In contrast, dominant-negative suppression of DRP-1 function as represented by DRP-1 K38A significantly prevented FFA-induced apoptosis in xenografts. It was further demonstrated that mitochondrial membrane potential decreased, while cytochrome c release, caspase-3 activation, and generation of reactive oxygen species (ROS) were enhanced by the induction of DRP-1WT, but prevented by DRP-1 K38A in INS-1-derived cells under FFA stimulation. These results indicated that DRP-1 mediates FFA-induced INS-1-derived cell apoptosis, suggesting that suppression of DRP-1 is a potentially useful therapeutic strategy for protecting against beta cell loss that leads to type 2 diabetes.Liang PengXiuli MenWenjian ZhangHaiyan WangShiqing XuQing FangHonglin LiuWenying YangJinning LouPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e49258 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Liang Peng Xiuli Men Wenjian Zhang Haiyan Wang Shiqing Xu Qing Fang Honglin Liu Wenying Yang Jinning Lou Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
description	Elevated extracellular free fatty acids (FFAs) can induce pancreatic beta cell apoptosis, thereby contributing to the pathogenesis of type 2 diabetes mellitus (T2D). Mitochondrial dysfunction has been implicated in FFA-induced beta cell apoptosis. However, molecular mechanisms linking mitochondrial dysfunction and FFA-induced beta cell apoptosis are not clear. Dynamin-related protein 1 (DRP-1) is a mitochondrial fission modulator. In this study, we investigated its role in FFA-induced INS-1 beta cell apoptosis. DRP-1 protein was promptly induced in INS-1 cells and rat islets after stimulation by FFAs, and this DRP-1 upregulation was accompanied by increased INS-1 cell apoptosis. Induction of DRP-1 expression significantly promoted FFA-induced apoptosis in DRP-1 WT (DRP-1 wild type) inducible INS-1-derived cell line, but not in DRP-1K38A (a dominant negative mutant of DRP-1) inducible INS-1-derived cell line. To validate these in vitro results, we transplanted DRP-1 WT or DRP-1 K38A cells into renal capsules of streptozotocin (STZ)-treated diabetic mice to study the apoptosis in xenografts. Consistent with the in vitro results, the over-expression of DRP-1 led to aggravated INS-1-derived cell apoptosis triggered by FFAs. In contrast, dominant-negative suppression of DRP-1 function as represented by DRP-1 K38A significantly prevented FFA-induced apoptosis in xenografts. It was further demonstrated that mitochondrial membrane potential decreased, while cytochrome c release, caspase-3 activation, and generation of reactive oxygen species (ROS) were enhanced by the induction of DRP-1WT, but prevented by DRP-1 K38A in INS-1-derived cells under FFA stimulation. These results indicated that DRP-1 mediates FFA-induced INS-1-derived cell apoptosis, suggesting that suppression of DRP-1 is a potentially useful therapeutic strategy for protecting against beta cell loss that leads to type 2 diabetes.
format	article
author	Liang Peng Xiuli Men Wenjian Zhang Haiyan Wang Shiqing Xu Qing Fang Honglin Liu Wenying Yang Jinning Lou
author_facet	Liang Peng Xiuli Men Wenjian Zhang Haiyan Wang Shiqing Xu Qing Fang Honglin Liu Wenying Yang Jinning Lou
author_sort	Liang Peng
title	Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
title_short	Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
title_full	Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
title_fullStr	Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
title_full_unstemmed	Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.
title_sort	involvement of dynamin-related protein 1 in free fatty acid-induced ins-1-derived cell apoptosis.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/cd19bf199059401fa2d602abc0109dc0
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_version_	1718422195511754752

Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis.

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