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, ITF2357 concentration 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. http://www.selleckchem.com/products/MK-2206.html 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) The earliest phases of hepatic involvement in Wilson’s disease (WD) include portal inflammation that may present as lymphocyte and neutrophil infiltrations,1 and microvesicular and macrovesicular steatosis,2 which is exhibited both clinically2 and in
animal models of WD.3, 4 Previous studies on the pathogenesis of WD explored the possibilities of genetic polymorphisms in the ATP7B copper (Cu) transporter,5 alternative ATP7B gene splice variants,6 alterations in the RNA processing machinery,7 and the presence of gene modifiers.8 selleck screening library The mechanisms connecting Cu accumulation to hepatocyte damage are poorly understood and may include oxidative damage,9 apoptosis,10 and mitochondrial membrane cross-linking.11 Abnormal methionine metabolism occurs in animal models of hepatic Cu overload,12, 13 is connected to epigenetic regulation of gene expression,14 and could represent a link between Cu accumulation and the variety of hepatic manifestations in WD. Methionine metabolism is central to the regulation of S-adenosylhomocysteine (SAH), which inhibits methylation reactions, and is known to sensitize hepatocytes to the presence of tumor necrosis factor alpha (TNF-α).