title: Targeting lipid metabolism in the treatment of hepatitis C virus infection.
abstract: Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called "lipid rafts") have been considered to act as a scaffold for the hepatitis C virus (HCV) replication complex. Using the HCV cell culture system, we investigated the effect of myriocin, a sphingomyelin synthesis inhibitor, on HCV replication. We also investigated the combined effect of myriocin with interferon (IFN) and myriocin with simvastatin. Myriocin suppressed replication of both a genotype 1b subgenomic HCV replicon (Huh7/Rep-Feo) and genotype 2a infectious HCV (JFH-1 HCV) in a dose-dependent manner (for subgenomic HCV-1b, maximum of 79% at 1000 nmol/L; for genomic HCV-2a, maximum of 40% at 1000 nmol/L). Combination treatment with myriocin and IFN or myriocin and simvastatin attenuated HCV RNA replication synergistically in Huh7/Rep-Feo cells. Our data demonstrate that the sphingomyelin synthesis inhibitor strongly suppresses replication of both the subgenomic HCV-1b replicon and the JFH-1 strain of genotype 2a infectious HCV, indicating that lipid metabolism could be a novel target for HCV therapy.
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Chuo, Japan.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Amemiya
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Itakura
authors.forename: Asuka
authors.initials: A
authors.lastname: Kanayama
authors.forename: Akira
authors.initials: A
authors.lastname: Matsui
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takano
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Itakura
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kitamura
authors.forename: Taisuke
authors.initials: T
authors.lastname: Inoue
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Kozue
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Okada
authors.forename: Atsuya
authors.initials: A
authors.lastname: Yamashita
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Itoh
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
mesh_terms: D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D006526:Hepatitis C / Q000628:therapy*; D006801:Humans; D008055:Lipids / Q000502:physiology*; D008113:Liver Neoplasms; D010957:Plasmids; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; C012491:phytosphingosine; D013110:Sphingosine