Methionine Adenosyltransferase as a Therapeutic Target for Liver Fibrosis

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Hepatic fibrosis is an outcome of many chronic liver diseases such as alcohol consumption, biliary obstruction and hepatitis. Prolonged liver injury triggers activation of hepatic stellate cells (HSC) and leads to modulation of key transcriptional regulators. Methionine adenosyl transferases (MAT) catalyze the formation of the principle biological methyl donor, S-adenosylmethionine (SAMe). Two genes, MAT2A and MAT2B, are known to be strongly associated with liver cell proliferation and malignant degeneration. In the K99 phase, we showed that MAT2A and MAT2B genes are induced during HSC activation both in vitro and in vivo, This is associated with a decrease in MAT activity and SAMe levels. Gene silencing studies showed that these genes are important for HSC activation. The MAT2A gene is transcriptionally regulated in normal, differentiated HSCs by binding of peroxisome proliferator activated receptor (PPAR-gamma) to the MAT2A promoter. During HSC activation, there is decreased activity and expression of PPAR-gamma and its regulatory control over MAT2A is abolished, leading to increased expression of MAT2A. We also show that HSC activation is associated with increased binding of PPAR-beta to the MAT2A promoter and silencing PPAR-beta blocks MAT2A induction in activated HSCs. In the ROO phase ofthis award, we will use biochemical and molecular biology techniques to address four specific aims: 1) To evaluate whether MAT genes are required for in vivo HSC activation in rat models of liver fibrosis and study their interplay with molecular signals in HSCs from fibrotic liver, 2) to examine whether known pro-fibrogenic factors, leptin and platelet-derived growrth factor (PDGF) can influence MAT gene expression in rat HSCs and whether SAMe and MTA can block this response, 3) 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, and 4) to establish'molecular mechanisms for regulatory control of MAT2A and MAT2B expression in human HSCs. My long term plan is to establish myself as an independent Investigator in the field of human liver fibrosis and cirrhosis.