Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria.

フォーマット:

論文

責任表示:

Nakamura, Seiji ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Takayama, Hiroaki ; Misu, Hirofumi ; Noda, Hiroyo ; Nabemoto, Satoko ; Kurita, Seiichiro ; Ota, Tsuguhito ; Ando, Hitoshi ; Miyamoto, Kenichi ; Kaneko, Shuichi

言語:

英語

出版情報:

American Society for Biochemistry and Molecular Biology, 2009-05-29

著者名:

Nakamura, Seiji

Takamura, Toshinari

Matsuzawa-Nagata, Naoto

Takayama, Hiroaki

Misu, Hirofumi

Noda, Hiroyo

Nabemoto, Satoko

Kurita, Seiichiro

Ota, Tsuguhito

Ando, Hitoshi

Miyamoto, Kenichi

Kaneko, Shuichi

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掲載情報:

The Journal of biological chemistry

ISSN:

0021-9258      

巻:

284

通号:

22

開始ページ:

14809

終了ページ:

14818

バージョン:

author

概要:

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. 続きを見る

URL:

http://hdl.handle.net/2297/18986