Fenofibrate induces apoptotic injury in cultured human hepatocytes by inhibiting phosphorylation of Akt

T. Kubota, T. Yano, K. Fujisaki, Y. Itoh, R. Oishi

研究成果: ジャーナルへの寄稿学術誌査読

20 被引用数 (Scopus)

抄録

Fibric acid derivatives have a potent and effective lipid-lowering action, however, the use of these compounds is sometimes limited due to the occurrence of hepatic injury. In the present study, we characterized cell injury induced by fenofibrate in cultured human hepatocytes. Fenofibrate caused a loss of cell viability and nuclear damage as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling or by DNA electrophoresis, in which caspase activation is involved. The cell injury was accompanied by the shrinkage and the translocation of phosphatidyl serine from inner membrane to the outer membrane as determined by annexin V stain. The mRNA expression for bcl-2 was reduced by fenofibrate. An immunofluorescent stain with antiserum raised against phosphorylated Akt revealed that fenofibrate inhibited insulin-stimulated phosphorylation of Akt. Like fenofibrate, several compounds that inhibit the phosphorylation of Akt, including wortmannin, SH-6 and a high concentration (100 μ M) of SB203580, reduced the viability of cultured human hepatocytes. Both nuclear damage and cell injury induced by fenofibrate were reversed by insulin in a concentration-dependent manner. In contrast, bezafibrate or 8(S)-hydroxyeicosatetraenoic acid had no hepatotoxic action. These findings suggest that fenofibrate causes caspase-dependent apoptosis in human hepatocytes by inhibiting phosphorylation of Akt, in which PPARα is not involved.

本文言語英語
ページ(範囲)349-358
ページ数10
ジャーナルApoptosis
10
2
DOI
出版ステータス出版済み - 3月 2005

!!!All Science Journal Classification (ASJC) codes

  • 薬理学
  • 薬科学
  • 臨床生化学
  • 細胞生物学
  • 生化学、医学
  • 癌研究

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