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Glucotoxicity-induced suppression of Cox6a2 expression provokes ß-cell dysfunction via augmented ROS production.
Nagai, Yasuki; Matsuoka, Taka-Aki; Shimo, Naoki; Miyatsuka, Takeshi; Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-Ichi; Katakami, Naoto; Shimomura, Iichiro.
Afiliación
  • Nagai Y; Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.
  • Matsuoka TA; First Department of Medicine, Wakayama Medical University, Wakayama, Japan. Electronic address: matsuoka@wakayama-med.ac.jp.
  • Shimo N; Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.
  • Miyatsuka T; Department of Metabolism and Endocrinology, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
  • Miyazaki S; Division of Stem Cell Regulation Research, Center for Medical Research and Education, Osaka University Graduate School of Medicine, Osaka, Japan.
  • Tashiro F; Division of Stem Cell Regulation Research, Center for Medical Research and Education, Osaka University Graduate School of Medicine, Osaka, Japan.
  • Miyazaki JI; The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.
  • Katakami N; Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan; Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, Osaka, Japan.
  • Shimomura I; Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.
Biochem Biophys Res Commun ; 556: 134-141, 2021 06 04.
Article en En | MEDLINE | ID: mdl-33839409
Oxidative stress is a deteriorating factor for pancreatic ß-cells under chronic hyperglycemia in diabetes. However, the molecular mechanism underlying the increase in oxidative stress in ß-cells under diabetic conditions remains unclear. We demonstrated previously that the selective alleviation of glucotoxicity ameliorated the downregulation of several ß-cell factors, including Cox6a2. Cox6a2 encodes a subunit of the respiratory chain complex IV in mitochondria. In this study, we analyzed the role of Cox6a2 in pancreatic ß-cell function and its pathophysiological significance in diabetes mellitus. Cox6a2-knockdown experiments in MIN6-CB4 cells indicated an increased production of reactive oxygen species as detected by CellROX Deep Red reagent using flow cytometry. In systemic Cox6a2-knockout mice, impaired glucose tolerance was observed under a high-fat high-sucrose diet. However, insulin resistance was reduced when compared with control littermates. This indicates a relative insufficiency of ß-cell function. To examine the transcriptional regulation of Cox6a2, ATAC-seq with islet DNA was performed and an open-chromatin area within the Cox6a2 enhancer region was detected. Reporter gene analysis using this area revealed that MafA directly regulates Cox6a2 expression. These findings suggest that the decreased expression of Cox6a2 increases the levels of reactive oxygen species and that Mafa is associated with decreased Cox6a2 expression under glucotoxic conditions.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Especies Reactivas de Oxígeno / Células Secretoras de Insulina / Proteínas Musculares Límite: Animals / Humans Idioma: En Revista: Biochem Biophys Res Commun Año: 2021 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Especies Reactivas de Oxígeno / Células Secretoras de Insulina / Proteínas Musculares Límite: Animals / Humans Idioma: En Revista: Biochem Biophys Res Commun Año: 2021 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos