title: Roles of Oxidized Diacylglycerol for Carbon Tetrachloride-induced Liver Injury and Fibrosis in Mouse.
abstract: Since there is a report that an inhibitor of protein kinase C (PKC) effectively suppresses the development of hepatic fibrosis, it is suggested that the PKC signaling pathway plays an important role in the pathogenesis of hepatic fibrosis. We reported that oxidized diacylglycerol (DAG), which is an activator of PKC, had a remarkably stronger PKC-activating action than un-oxidized DAG. In the present study, we explored the roles of oxidized DAG in hepatic fibrogenesis using mice, the livers of which developed fibrosis by long-term administration of carbon tetrachloride (CCl4). Liver fibrosis models were created by 4- or 8-week repetitive subcutaneous injections of CCl4 to the backs of C57BL/6J mice. The amount of oxidized DAG was significantly increased in the CCl4-treated group. Moreover, it was found that PKCα, βI, βII and δ were activated. In the CCl4-treated group, phosphorylation of ERK and JNK, which are downstream signal transmitters in the PKC pathway, was increased. It was also found in this group that there was an increase in TIMP-1, which is a fibrogenesis-promoting factor whose expression is enhanced by activated JNK, and of TNF-α, an inflammatory cytokine. Analysis by quantitative real-time RT-PCR showed that expressions of αSMA, collagen I, TNF-α and IL-10 were remarkably increased in the 8-week CCl4-treated group. The above results strongly suggested that oxidized DAG, which is increased by augmented oxidative stress, activated PKCα, βI, βII and δ molecular species and that these molecular species in turn stimulated the phosphorylation of MAP kinases including ERK and JNK, resulting in enhancement of hepatic fibrogenesis.
authors: Department of Cell Biology, Division of Host Defense Mechanism, Tokai University School of Medicine , 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors: Susumu
authors: S
authors: Takekoshi
authors: Department of Cell Biology, Division of Host Defense Mechanism, Tokai University School of Medicine , 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors: Kanae
authors: K
authors: Kitatani
authors: School of Bioscience and Biotechnology, Tokyo University of Technology , 1404-1 Katakura-cho, Hachioji, Tokyo 192-0982, Japan.
authors: Yorihiro
authors: Y
authors: Yamamoto
keywords: carbon tetrachloride; diacylglycerol; liver fibrosis; oxidative stress; protein kinase C