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), encoded by MAT1A in liver. 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, development of non-alcoholic steatohepatitis (NASH) 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, NASH, fibrosis and also HCC. This model is relevant to human disease as children with GNMT mutations have liver injury. These models have been instrumental in teaching us about the various functions of SAMe in the liver. This grant is currently in its 10th year and we have published 63 original papers plus 23 reviews. During the past funding period we showed how dysregulation of SAMe could lead to liver injury and malignant degeneration. We also found that chronically high and low hepatic SAMe levels lead to NASH via different alterations in lipid metabolism that is reflected in their lipidomic profiles. Our finding led us to hypothesize that altered hepatic SAMe level is an important determinant in the progression of steatosis to NASH. This is supported by recent reports that the expression of MAT1A and GNMT is lower in patients with more severe NASH. In addition, we hypothesize that lipidomic profiling from the two KO models can help categorize NASH patients and personalize NASH treatment.
Three specific aims are proposed to test these hypotheses: 1. Examine the influence of SAMe level on personalized NASH treatment. Our hypothesis is that one form of treatment will benefit MAT1A KO but not GNMT KO and vice versa. We will test different proposed NASH treatment protocols in the two KO models to see how they affect their lipidomics and NASH progression. 2. Examine the influence of SAMe level on progression from steatosis to NASH. We will test the hypothesis that when hepatic SAMe level is altered by reducing either MAT1A or GNMT expression, this will convert animal models of simple steatosis to NASH. We will use two different fatty liver models to test this. 3. Examine the influence of SAMe level on serum lipid signature. We will examine and compare serum lipidomics in MAT1A KO to GNMT KO mice to generate M-type (for MAT1A) and G-type (for GNMT) serum lipid signatures. We will examine serum lipid profiles from 467 patients to see if they can be categorized into these types. Successful completion of these proposed aims will further enhance our knowledge of how altered SAMe metabolism affects NAFLD progression and help personalize NASH treatment, which are highly relevant to public health.

Public Health Relevance

-Adenosylmethionine (SAMe) is made in all cells and is involved in many critical reactions including control of lipid metabolism, growth and death. In the liver, SAMe level needs to be controlled as too much and too little can both result in fatty liver and liver cancer. Non-alcoholic fatty liver disease is the most common liver disease in the United States and it can progress to the more severe form called non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer for which effective treatment is still lacking. The ultimate goa of this project is to understand how abnormal liver SAMe level affects lipid metabolism and progression of fatty liver disease so that we can use this knowledge to personalize treatment of NASH patients.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hopp, Craig
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Fernández-Ramos, David; Fernández-Tussy, Pablo; Lopitz-Otsoa, Fernando et al. (2018) MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis. Cell Death Dis 9:958
Mayo, Rebeca; Crespo, Javier; Martínez-Arranz, Ibon et al. (2018) Metabolomic-based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts. Hepatol Commun 2:807-820
Maldonado, Lauren Y; Arsene, Diana; Mato, José M et al. (2018) Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy. Exp Biol Med (Maywood) 243:107-117
Gutiérrez-de-Juan, Virginia; López de Davalillo, Sergio; Fernández-Ramos, David et al. (2017) A morphological method for ammonia detection in liver. PLoS One 12:e0173914
Barbier-Torres, Lucía; Iruzubieta, Paula; Fernández-Ramos, David et al. (2017) The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury. Nat Commun 8:2068
Iruarrizaga-Lejarreta, Marta; Varela-Rey, Marta; Fernández-Ramos, David et al. (2017) Role of Aramchol in steatohepatitis and fibrosis in mice. Hepatol Commun 1:911-927
Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Martín-Martín, Natalia et al. (2017) mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547:109-113
Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Barbier-Torres, Lucía et al. (2017) Deregulated neddylation in liver fibrosis. Hepatology 65:694-709
Alonso, Cristina; Fernández-Ramos, David; Varela-Rey, Marta et al. (2017) Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis. Gastroenterology 152:1449-1461.e7
Zubiete-Franco, Imanol; García-Rodríguez, Juan Luis; Martínez-Uña, Maite et al. (2016) Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. J Hepatol 64:409-418

Showing the most recent 10 out of 104 publications