BACKGROUND: To demonstrate a causative role for abnormal methionine metabolism in the pathogenesis of alcoholic steatohepatitis (ASH), we measured the preventive effects of supplementing folate deficient and ethanol containing diets in the micropig with S-adenosylmethionine (SAM), a metabolite that regulates methionine metabolism. METHODS: Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, or with ethanol supplemented with SAM at 0.4 g/1000 kcal for 14 weeks. Histopathology, markers of liver injury, and regulatory enzymes were measured in terminal liver samples. RESULTS: Among the ethanol group, livers showed hepatocellular necrosis together with increased levels of S-adenosylhomocysteine (SAH) and reduced levels of SAM and its ratio to SAH and glutathione (GSH), together with increased malondialdehyde plus hydroxynonenol (MDA + HNE) and nitrotyrosine (NT), transcripts and protein levels of cytochrome P4502E1 (CYP2E1), activity of NADPH oxidase, and activity and protein levels of inducible nitric oxide (iNOS). These findings were attenuated partially or completely to control levels by SAM supplementation of the ethanol diet. CONCLUSIONS: The present results indicate that SAM supplementation attenuates ethanol induced liver injury through its effects on the expressions and activities of oxidative stress pathways, and are consistent with the concept that the pathogenesis of oxidative liver injury is regulated in part through altered hepatic methionine metabolism.
BACKGROUND: To demonstrate a causative role for abnormal methionine metabolism in the pathogenesis of alcoholic steatohepatitis (ASH), we measured the preventive effects of supplementing folate deficient and ethanol containing diets in the micropig with S-adenosylmethionine (SAM), a metabolite that regulates methionine metabolism. METHODS: Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, or with ethanol supplemented with SAM at 0.4 g/1000 kcal for 14 weeks. Histopathology, markers of liver injury, and regulatory enzymes were measured in terminal liver samples. RESULTS: Among the ethanol group, livers showed hepatocellular necrosis together with increased levels of S-adenosylhomocysteine (SAH) and reduced levels of SAM and its ratio to SAH and glutathione (GSH), together with increased malondialdehyde plus hydroxynonenol (MDA + HNE) and nitrotyrosine (NT), transcripts and protein levels of cytochrome P4502E1 (CYP2E1), activity of NADPH oxidase, and activity and protein levels of inducible nitric oxide (iNOS). These findings were attenuated partially or completely to control levels by SAM supplementation of the ethanol diet. CONCLUSIONS: The present results indicate that SAM supplementation attenuates ethanol induced liver injury through its effects on the expressions and activities of oxidative stress pathways, and are consistent with the concept that the pathogenesis of oxidative liver injury is regulated in part through altered hepatic methionine metabolism.
Authors: Valentina Medici; Maria C Virata; Janet M Peerson; Sally P Stabler; Samuel W French; Jesse F Gregory; Anthony Albanese; Christopher L Bowlus; Sridevi Devaraj; Edward A Panacek; John R Richards; Charles H Halsted Journal: Alcohol Clin Exp Res Date: 2011-11 Impact factor: 3.455
Authors: Mary D Le; Elena Enbom; Peter K Traum; Valentina Medici; Charles H Halsted; Samuel W French Journal: Exp Mol Pathol Date: 2013-07-23 Impact factor: 3.362
Authors: Valentina Medici; Janet M Peerson; Sally P Stabler; Samuel W French; Jesse F Gregory; Maria Catrina Virata; Antony Albanese; Christopher L Bowlus; Sridevi Devaraj; Edward A Panacek; Nazir Rahim; John R Richards; Lorenzo Rossaro; Charles H Halsted Journal: J Hepatol Date: 2010-05-31 Impact factor: 25.083
Authors: Farah Esfandiari; Valentina Medici; Donna H Wong; Soumia Jose; Maryam Dolatshahi; Eoin Quinlivan; Sanjana Dayal; Steven R Lentz; Hidekazu Tsukamoto; Yue Hua Zhang; Samuel W French; Charles H Halsted Journal: Hepatology Date: 2010-03 Impact factor: 17.425
Authors: Kusum K Kharbanda; Vasanthy Vigneswara; Benita L McVicker; Anna U Newlaczyl; Kevin Bailey; Dean Tuma; David E Ray; Wayne G Carter Journal: Biochem Biophys Res Commun Date: 2009-02-23 Impact factor: 3.575