Role of SAMe in Pathogenesis and Treatment of Non-Alcholic Fatty Liver Disease

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

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Abstract

ABSTRACT S-adenosylmethionine (SAMe) is the principal biological methyl donor, precursor of polyamines and GSH. Liver plays a central role in SAMe metabolism, as this is where the bulk of SAMe is generated as the product of methionine catabolism. This reaction is catalyzed by methionine adenosyltransferase (MAT). Two genes encode for MAT, MAT1A is expressed in normal differentiated liver and MAT2A is expressed in all extrahepatic tissues. In liver, SAMe homeostasis is controlled by MAT-mediated biosynthesis and utilization, largely accomplished by glycine N-methyltransferase (GNMT). We developed the MAT1A knockout (KO) mouse model, which exhibits chronic hepatic SAMe deficiency, increased oxidative stress, spontaneous development of steatohepatitis and hepatocellular carcinoma (HCC). This model recapitulates the situation in many patients with chronic liver disease as hepatic SAMe biosynthesis is impaired. We also developed the GNMT KO mouse model, where hepatic SAMe accumulates to supraphysiological level and the mice develop liver injury, fibrosis and also HCC. This model is relevant to human disease as children with GNMT mutations were recently identified to have liver injury. These models have been instrumental in teaching us about the various functions of SAMe and pathways that it regulates in the liver. This grant is currently in its 9th year and we have published 60 original papers plus 22 reviews (42 original and 14 reviews in the past funding period). During the past funding period we uncovered numerous novel actions of SAMe that include regulation of progenitor cell population, hepatocyte growth factor-mediated signaling, HuR, LKB1/AMPK, ERK, and AKT activities, histone post-translational modifications, genomic instability, protein sumoylation, and lipid metabolism. We improved our understanding of how liver injury occurs and HCC develops when SAMe level is chronically altered. Clearly, SAMe is much more than just a methyl donor and this renewal grant will continue our study on how alteration of hepatic SAMe level affects liver function, injury and cancer development. Three specific aims are proposed: 1. Examine how altered SAMe levels affect lipid metabolism. Both MAT1A and GNMT KO mice develop steatohepatitis. VLDL assembly is impaired when hepatic SAMe is depleted. This aim will examine how steatosis develops when SAMe excess occurs. 2. Examine how SAMe affects sumoylation, Myc and their interplay. Increased protein sumoylation occurs in MAT1A KO mice. We will elucidate the mechanism(s) involved and examine how this interacts with the Myc pathway. 3. Examine how SAMe affects protein phosphorylation, activity of MAPKs and receptor tyrosine kinases (RTKs). Our preliminary data indicate activity of MAPKs and RTKs are affected by SAMe. SAMe depletion favors increased phosphorylation while SAMe treatment lowers phosphorylation. We will elucidate the mechanisms involved. Successful completion of these proposed aims will further enhance our knowledge of how altered SAMe metabolism affects liver function and help to identify patients that will benefit from its therapeutic use, which are highly relevant to public health.