Loss of the glycine N‐methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice†

Abstract

Glycine N-methyltransferase (GNMT) is the main enzyme responsible for catabolism of excess hepatic S-adenosylmethionine (SAMe). GNMT is absent in hepatocellular carcinoma (HCC), messenger RNA (mRNA) levels are significantly lower in livers of patients at risk of developing HCC, and GNMT has been proposed to be a tumor-susceptibility gene for liver cancer. The identification of several children with liver disease as having mutations of the GNMT gene further suggests that this enzyme plays an important role in liver function. In the current study we studied development of liver pathologies including HCC in GNMTknockout (GNMT-KO) mice. GNMT-KO mice have elevated serum aminotransferase, methionine, and SAMe levels and develop liver steatosis, fibrosis, and HCC. We found that activation of the Ras and Janus kinase ( T he first steps in mammalian methionine metabolism are conversion to S-adenosylmethionine (SAMe) and transfer of the methyl group of SAMe to a large variety of substrates (including DNA, RNA, histones, and small molecules such as glycine, guanidinoacetate, and phosphatidylethanolamine) with the formation of S-adenosylhomocysteine (SAH), an inhibitor of many SAMe-dependent methyltransferases. 1 Although there are a large number of SAMe-dependent methyltransferases, 2 methylation of glycine by glycine Nmethyltransferase (GNMT) to form sarcosine (N-methylglycine) is one of the reactions that contribute most to total transmethylation flux. 3 The importance of GNMT is to remove excess SAMe and maintain a constant hepatic SAMe/SAH ratio to avoid aberrant methylation. 2 Consistent with this function, the activation of GNMT in rats by the administration of retinoic acid causes a reduction in plasma methionine and homocysteine levels, as well as in liver DNA methylation. 4,5 In GNMT-knockout (GNMT-KO) mice, liver SAMe content is elevated 35-fold, and the SAMe/SAH ratio increases about 100-fold, 6 and individuals with GNMT mutations, which leads to inactive forms of the enzyme, have elevated plasma levels of methionine and SAMe but a normal concentration of homocysteine. 7,8 GNMT is expressed in the liver, pancreas, and prostate 9 and is absent in hepatocellular carcinoma (HCC) 10 and down-regulated in the livers of patients at risk of Abbreviations: GNMT, HCC, hepatocellular carcinoma; H3K27me3, trimethylated Received September 10, 2007; accepted November 26, 2007. Supported by NIH grants AA12677, AA13847, and AT-1576 (to S.C.L. and J.M.M.); DK15289 (to C.W.), PN IϩD SAF 2005-00855, HEPADIP-EULSHM-CT-205, and ETORTEK 2005 (to J.M.M. and M.L.M.-C.); Program Ramón y Cajal (to M.L.M.-C.); and Fundación "La Caixa" (to M.L.M.-C., R.M., and A.M.A.).

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

“…GNMT may have an important role in promoting prostate cancer cell growth via the regulation of apoptosis. Our results seem to disagree with previous findings that GNMT is a tumor susceptibility gene, [10][11][12] but agree with the previous findings that GNMT activity is linked with the progression of cancer. 5 According to our findings, we hypothesize that GNMT expression may correlate with malignant progression and prognosis.…”

“…9 A loss of heterozygosity at the GNMT in pairs of normal and tumor tissue from HCC patients has also been observed, 10 and GNMT knockout mice develop liver cancer. 11 A significant proportion of human prostate cancers show a loss of heterozygosity of the GNMT gene. 12 Furthermore, immunohistochemical results show abundant GNMT expression in normal tissues, whereas this expression is diminished in prostate cancer tissues 12 and cholangiocarcinoma tissues.…”

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

“…GNMT deficiency in mice results in chronic hepatitis, fatty liver and HCC spontaneously (25,26,30). Recently, several putative metabolites identified in Gnmt -/-mice serum closely resemble those of NAFLD patients (31).…”

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

“…GNMT is also a major hepatic folate-binding protein (2,3) that binds to, and, subsequently, may be inhibited by 5-methyl-THF (2). The expression and function of GNMT have been investigated in human diseases (4-7) and mouse models (8)(9)(10). Downregulation of GNMT has also been reported in human hepatocellular carcinoma.…”