論文

国際誌
2017年8月

Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate-activated protein kinase-related kinases and retinoid X receptor α.

Hepatology communications
  • Shinya Satoh
  • ,
  • Kyoko Mori
  • ,
  • Daichi Onomura
  • ,
  • Youki Ueda
  • ,
  • Hiromichi Dansako
  • ,
  • Masao Honda
  • ,
  • Shuichi Kaneko
  • ,
  • Masanori Ikeda
  • ,
  • Nobuyuki Kato

1
6
開始ページ
550
終了ページ
563
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/hep4.1065

Ribavirin (RBV) has been widely used as an antiviral reagent, specifically for patients with chronic hepatitis C. We previously demonstrated that adenosine kinase, which monophosphorylates RBV into the metabolically active form, is a key determinant for RBV sensitivity against hepatitis C virus RNA replication. However, the precise mechanism of RBV action and whether RBV affects cellular metabolism remain unclear. Analysis of liver gene expression profiles obtained from patients with advanced chronic hepatitis C treated with the combination of pegylated interferon and RBV showed that the adenosine kinase expression level tends to be lower in patients who are overweight and significantly decreases with progression to advanced fibrosis stages. In our effort to investigate whether RBV affects cellular metabolism, we found that RBV treatment under clinically achievable concentrations suppressed lipogenesis in hepatic cells. In this process, guanosine triphosphate depletion through inosine monophosphate dehydrogenase inhibition by RBV and adenosine monophosphate-activated protein kinase-related kinases, especially microtubule affinity regulating kinase 4, were required. In addition, RBV treatment led to the down-regulation of retinoid X receptor α (RXRα), a key nuclear receptor in various metabolic processes, including lipogenesis. Moreover, we found that guanosine triphosphate depletion in cells induced the down-regulation of RXRα, which was mediated by microtubule affinity regulating kinase 4. Overexpression of RXRα attenuated the RBV action for suppression of lipogenic genes and intracellular neutral lipids, suggesting that down-regulation of RXRα was required for the suppression of lipogenesis in RBV action. Conclusion: We provide novel insights about RBV action in lipogenesis and its mechanisms involving inosine monophosphate dehydrogenase inhibition, adenosine monophosphate-activated protein kinase-related kinases, and down-regulation of RXRα. RBV may be a potential reagent for anticancer therapy against the active lipogenesis involved in hepatocarcinogenesis. (Hepatology Communications 2017;1:550-563).

リンク情報
DOI
https://doi.org/10.1002/hep4.1065
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29404478
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678905
ID情報
  • DOI : 10.1002/hep4.1065
  • PubMed ID : 29404478
  • PubMed Central 記事ID : PMC5678905

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