S-adenosylmethionine (SAMe) is the principal biological methyl donor, precursor for polyamines and glutathione (GSH). SAMe biosynthesis is catalyzed by methionine adenosyltransferase (MAT). Of the two genes (MAT1A, MAT2A) that encode MAT, MAT1A is expressed in adult liver. Cirrhotic patients have decreased hepatic MAT1A expression and SAMe biosynthesis. We have shown that MAT1A knockout (KO) mice with chronic hepatic SAMe deficiency have increased oxidative stress, develop steatohepatitis and hepatocellular carcinoma (HCC). During the past funding period we have uncovered many novel actions of SAMe that are independent of its role as a methyl donor or GSH precursor. This is because methylthioadenosine (MTA), a metabolite of SAMe that is not a methyl donor or GSH precursor, can recapitulate the same actions. SAMe regulates hepatocyte growth, death, inflammatory responses, and anti- oxidant defense. We have elucidated some of the molecular mechanisms of how SAMe regulates these responses and identified downstream targets that contribute to the increase in oxidative stress in MAT1A KO mice. In addition, we have preliminary data that show impaired SAMe metabolism, which occurs in glycine N- methyltransferase (GNMT) KO mice and patients with GNMT mutations, can lead to steatohepatitis, increased hepatocyte apoptosis, fibrosis, and HCC. Furthermore, our preliminary data show SAMe and MTA modulate histone methylation and acetylation to affect gene expression. Finally, we have found a dramatic increase in progenitor cell population as MAT1A KO mice age and that these cells can be tumorigenic in vivo. This proposal is a logical extension of our work to better define the role of SAMe in liver health and pathology.
Four specific aims are proposed: 1. Examine SAMe's regulation of HGF-mediated hepatocyte proliferation. Hepatocyte growth factor (HGF) activates AMP kinase (AMPK), which is required for hepatocyte proliferation. Our new data also show cross-talks between AMPK and nitric oxide synthase in modulating the proliferative effect of HGF. How SAMe regulates these pathways will be elucidated. 2. Examine SAMe's modulation of histone post-translational modifications. How SAMe affects histone methylation and acetylation to regulate TNF1 and iNOS expression will be examined. 3. Examine how altered SAMe metabolism affects the susceptibility to liver injury. We will investigate the mechanisms for liver injury in GNMT KO mice and compare them to MAT1A KO mice. 4. Identify mechanisms of malignant degeneration when SAMe metabolism is altered. Both chronic SAMe deficiency and excess result in HCC.
This aim will examine how malignancy develops in these two models. Patients with chronic liver disease have impaired SAMe biosynthesis. Patients with GNMT mutations also develop liver injury. Successful completion of these proposed aims should greatly enhance our understanding of SAMe's role in liver health and pathology and help identify patients that will benefit from its therapeutic use, which are highly relevant to public health. Public Health Relevance: S-adenosylmethionine (SAMe) is made in all cells and is involved in many critical reactions including control of growth and death. In the liver, SAMe level needs to be controlled as too much and too little can both result in liver injury and cancer. The goal of this project is to understand how SAMe controls these processes and how injury and cancer occur when SAMe metabolism is perturbed.
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| 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 |
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| Alonso, Cristina; Fernández-Ramos, David; Varela-Rey, Marta et al. (2017) Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis. Gastroenterology 152:1449-1461.e7 |
| 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 |
| 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 |
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