Takashi Takano1, Kyoko Tsukiyama-Kohara2, Masahiro Hayashi1, Yuichi Hirata1, Masaaki Satoh3, Yuko Tokunaga1, Chise Tateno4, Yukiko Hayashi5, Tsunekazu Hishima5, Nobuaki Funata5, Masayuki Sudoh6, Michinori Kohara1. 1. Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. 2. Department of Experimental Phylaxiology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Kumamoto 860-8556, Japan. Electronic address: kkohara@kumamoto-u.ac.jp. 3. Department of Experimental Phylaxiology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Kumamoto 860-8556, Japan. 4. Phoenix Bio Co., Ltd., Study Service Department, 3-4-1 Kagamiyama, Higashi-Hiroshima 739-0046, Japan. 5. Department of Pathology, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. 6. Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kajiwara 200, Kamakura-City, Kanagawa 247-8530, Japan.
Abstract
BACKGROUND & AIMS: We characterized the role of 24-dehydrocholesterol reductase (DHCR24) in hepatitis C virus infection (HCV). DHCR24 is a cholesterol biosynthetic enzyme and cholesterol is a major component of lipid rafts, which is reported to play an important role in HCV replication. Therefore, we examined the potential of DHCR24 as a target for novel HCV therapeutic agents. METHODS: We examined DHCR24 expression in human hepatocytes in both the livers of HCV-infected patients and those of chimeric mice with human hepatocytes. We targeted DHCR24 with siRNA and U18666A which is an inhibitor of both DHCR24 and cholesterol synthesis. We measured the level of HCV replication in these HCV replicon cell lines and HCV infected cells. U18666A was administrated into chimeric mice with humanized liver, and anti-viral effects were assessed. RESULTS: Expression of DHCR24 was induced by HCV infection in human hepatocytes in vitro, and in human hepatocytes of chimeric mouse liver. Silencing of DHCR24 by siRNA decreased HCV replication in replicon cell lines and HCV JFH-1 strain-infected cells. Treatment with U18666A suppressed HCV replication in the replicon cell lines. Moreover, to evaluate the anti-viral effect of U18666A in vivo, we administrated U18666A with or without pegylated interferon to chimeric mice and observed an inhibitory effect of U18666A on HCV infection and a synergistic effect with interferon. CONCLUSIONS: DHCR24 is an essential host factor which augmented its expression by HCV infection, and plays a significant role in HCV replication. DHCR24 may serve as a novel anti-HCV drug target.
BACKGROUND & AIMS: We characterized the role of 24-dehydrocholesterol reductase (DHCR24) in hepatitis C virus infection (HCV). DHCR24 is a cholesterol biosynthetic enzyme and cholesterol is a major component of lipid rafts, which is reported to play an important role in HCV replication. Therefore, we examined the potential of DHCR24 as a target for novel HCV therapeutic agents. METHODS: We examined DHCR24 expression in human hepatocytes in both the livers of HCV-infectedpatients and those of chimeric mice with human hepatocytes. We targeted DHCR24 with siRNA and U18666A which is an inhibitor of both DHCR24 and cholesterol synthesis. We measured the level of HCV replication in these HCV replicon cell lines and HCV infected cells. U18666A was administrated into chimeric mice with humanized liver, and anti-viral effects were assessed. RESULTS: Expression of DHCR24 was induced by HCV infection in human hepatocytes in vitro, and in human hepatocytes of chimeric mouse liver. Silencing of DHCR24 by siRNA decreased HCV replication in replicon cell lines and HCV JFH-1 strain-infected cells. Treatment with U18666A suppressed HCV replication in the replicon cell lines. Moreover, to evaluate the anti-viral effect of U18666A in vivo, we administrated U18666A with or without pegylated interferon to chimeric mice and observed an inhibitory effect of U18666A on HCV infection and a synergistic effect with interferon. CONCLUSIONS:DHCR24 is an essential host factor which augmented its expression by HCV infection, and plays a significant role in HCV replication. DHCR24 may serve as a novel anti-HCV drug target.
Authors: Andreas Körner; Enchen Zhou; Christoph Müller; Yassene Mohammed; Sandra Herceg; Franz Bracher; Patrick C N Rensen; Yanan Wang; Valbona Mirakaj; Martin Giera Journal: Proc Natl Acad Sci U S A Date: 2019-09-23 Impact factor: 11.205
Authors: Winnie Luu; Eser J Zerenturk; Ika Kristiana; Martin P Bucknall; Laura J Sharpe; Andrew J Brown Journal: J Lipid Res Date: 2013-12-20 Impact factor: 5.922