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タイトル: Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria.
著者: Nakamura, Seiji
Takamura, Toshinari link image link image
Matsuzawa-Nagata, Naoto
Takayama, Hiroaki
Misu, Hirofumi link image link image
Noda, Hiroyo
Nabemoto, Satoko
Kurita, Seiichiro
Ota, Tsuguhito link image
Ando, Hitoshi
Miyamoto, Kenichi link image
Kaneko, Shuichi link image link image
篁, 俊成
長田, 直人
高山, 浩昭
御簾, 博文
太田, 嗣人
宮本, 謙一
金子, 周一
発行日: 2009年 5月29日
出版社(者): American Society for Biochemistry and Molecular Biology
雑誌名: The Journal of biological chemistry
ISSN: 0021-9258
巻: 284
号: 22
開始ページ: 14809
終了ページ: 14818
抄録: Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cause fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M901488200
URI: http://hdl.handle.net/2297/18986
資料種別: Journal Article
版表示: author
出現コレクション:1. 査読済論文(医学・保健)

このアイテムを引用あるいはリンクする場合は次の識別子を使用してください。 http://hdl.handle.net/2297/18986



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