Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells

Sakiko Arisawa, Kumiki Ishida, Natsumi Kameyama, Jun Ueyama, Ai Hattori, Yasuaki Tatsumi, Hisao Hayashi, Motoyoshi Yano, Kazuhiko Hayashi, Yoshiaki Katano, Hidemi Goto, Kenji Takagi, Shinya Wakusawa

研究成果: Article査読

49 被引用数 (Scopus)

抄録

Ursodeoxycholic acid (UDCA) is widely recognized as an effective compound in the treatment of chronic hepatitis and is known to modulate the redox state of the liver accompanied by an increase of GSH. In the present study, to access the antioxidative effect of UDCA and to clarify the molecular basis of the action on GSH level, we evaluated its effects in HepG2 cells exposed to excessive iron. UDCA inhibited both a decrease in the GSH level and an increase in the reactive oxygen species caused by excessive iron in the cells. UDCA increased the gene expression of the catalytic- and modifier-units of glutamine-cysteine ligase (GCL), which is a key enzyme in GSH synthesis. We further investigated the effect of UDCA on the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and obtained results showing that UDCA-induced increase in the GSH level was prevented by LY294002, a PI3K inhibitor. In addition, Western blot analysis of Akt showed that, while the total Akt level remained unchanged, the phosphorylated Akt level was increased by UDCA, and this increase was also prevented by LY294002. Moreover, UDCA promoted the translocation of a transcription factor, nuclear factor-E2-related factor-2 (Nrf2), into the nucleus, and this action was inhibited by LY294002. From these results, it was indicated that UDCA increased the GSH synthesis through an activation of the PI3K/Akt/Nrf2 pathway. This may be a primary mechanism of antioxidative action of UDCA concerned with its therapeutic effectiveness in chronic hepatitis.

本文言語English
ページ(範囲)858-866
ページ数9
ジャーナルBiochemical Pharmacology
77
5
DOI
出版ステータスPublished - 01-03-2009
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学
  • 薬理学

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