Steatohepatitis/Metabolic Liver Disease
Article first published online: 10 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 555–565, February 2013
How to Cite
Medici, V., Shibata, N. M., Kharbanda, K. K., LaSalle, J. M., Woods, R., Liu, S., Engelberg, J. A., Devaraj, S., Török, N. J., Jiang, J. X., Havel, P. J., Lönnerdal, B., Kim, K. and Halsted, C. H. (2013), Wilson's disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology, 57: 555–565. doi: 10.1002/hep.26047
Potential conflict of interest: Nothing to report.
Supported by grant number K08DK084111 from the National Institute of Diabetes and Digestive and Kidney Diseases, by Department and Divisional funds, by University of California Davis Center for Health and Nutrition Research (CHNR), by the National Center for Research Resources (NIH) through grant #UL1 RR024146 (to V.M.), by grant number R03AA020577-01 from the National Institute on Alcohol Abuse and Alcoholism (to C.H.H.), by 2R01HD041462 from the National Institute of Child Health and Human Development (to J.M.L.), T32ES002321 from the National Institute of Environmental Health Sciences (to R.W.), and by a Veterans Health Administration Biomedical Laboratory Research and Development National Merit Review grant (to K.K.K.). V.M. is a full member of the University of California San Francisco Liver Center (Liver Center grant number P30 DK026743). The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Issue published online: 5 FEB 2013
- Article first published online: 10 JAN 2013
- Accepted manuscript online: 4 SEP 2012 01:03AM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Received: 20 APR 2012
Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson's disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related to liver injury, levels of SAHH, SAH, DNA methyltransferases genes (Dnmt1, Dnmt3a, Dnmt3b), and global DNA methylation in the tx-j mouse (tx-j), an animal model of WD. Findings were compared to those in control C3H mice, and in response to Cu chelation by penicillamine (PCA) and dietary supplementation of the methyl donor betaine to modulate inflammatory and methylation status. Transcript levels of selected genes related to endoplasmic reticulum stress, lipid synthesis, and fatty acid oxidation were down-regulated at baseline in tx-j mice, further down-regulated in response to PCA, and showed little to no response to betaine. Hepatic Sahh transcript and protein levels were reduced in tx-j mice with consequent increase of SAH levels. Hepatic Cu accumulation was associated with inflammation, as indicated by histopathology and elevated serum alanine aminotransferase (ALT) and liver tumor necrosis factor alpha (Tnf-α) levels. Dnmt3b was down-regulated in tx-j mice together with global DNA hypomethylation. PCA treatment of tx-j mice reduced Tnf-α and ALT levels, betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels. Conclusion: Reduced hepatic Sahh expression was associated with increased liver SAH levels in the tx-j model of WD, with consequent global DNA hypomethylation. Increased global DNA methylation was achieved by reducing inflammation by Cu chelation or by providing methyl groups. We propose that increased SAH levels and inflammation affect widespread epigenetic regulation of gene expression in WD. (HEPATOLOGY 2013)