Methionine Adenosyltransferase as a Therapeutic Target for Liver Fibrosis

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DESCRIPTION (provided by applicant): Project Summary: Hepatic fibrosis is an outcome of many chronic liver diseases, such as viral and autoimmune hepatitis, and of alcohol consumption and biliary obstruction. Prolonged liver injury triggers activation of hepatic stellate cells (HSC) and recruitment of inflammatory cells into the liver. At the molecular level, these changes involve modulation of the expression or activity of key transcriptional regulators of the genome. Methionine adenosyl transferases (MAT) are essential enzymes that catalyze the formation of the principle biological methyl donor, S-adenosylmethionine (SAMe). Two of the MAT genes, MAT2A and MAT2p are known to be strongly associated with liver cell proliferation and malignant degeneration. Recently we discovered that MAT2A and MAT2P genes are essential for proliferation of liver cancer cells mediated by a well known pro-fibrogenic factor, leptin. These novel findings led us to hypothesize that the expression of MAT genes is induced during HSC activation and this may be an important event during fibrogenesis. Thus, we plan to use biochemical and molecular biology techniques to address four specific aims: 1) to evaluate the expression of MAT genes during activation of rat HSCs in vitro and in vivo and to determine whether they are required for activation, 2) to establish whether the metabolites in the MAT signaling pathway, SAMe and methylthioadenosine (MTA) can alter MAT gene expression and HSC activation, 3) to examine whether known pro-fibrogenic factors, leptin and platelet-derived growth factor (PDGF) can influence MAT gene expression in rat HSCs and whether SAMe and MTA can block this response and 4) to evaluate the expression of MAT genes in human HSC cell lines during activation in response to pro-fibrogenic signals, leptin and platelet-derived growth factor (PDGF) and further understand these mechanisms in HSCs isolated from human liver. We will initiate the first two aims during the mentored phase and I will further develop the subsequent aims during the independent phase of the award. My long term plan is to establish myself as an independent investigator in the field of human liver fibrosis and cirrhosis. RELEVANCE (Seeinstructions): The proposed experiments will provide a better understanding of the mechanisms underlying hepatic fibrosis its associated complications and will be useful in the development of therapeutic strategies for treatment of human liver fibrosis.