Wilson's disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease

Abstract

Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson 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 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.

Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver

“…On the other hand, there is a large body of literature demonstrating profound DNA methylation alterations in liver pathology. For instance, global DNA hypo-methylation has been reported in liver injury induced by Wilson's disease (Medici et al, 2012), as well as in liver cells following treatment with triclosan, which is thought to cause liver tumors (Ma et al, 2013). Furthermore, it has been shown that hypo-methylation plays a crucial role in the onset of liver fibrosis and the progression of the disease to cancer (Komatsu et al, 2012).…”

Oxidative Stress and Epigenetic Instability in Human Hepatocarcinogenesis

“…In this model, the methylation level was increased by copper chelation or by treatment with a methyl group donor. This suggested that Wilson's disease is a condition associated with an increased demand for methyl groups due to an increase in the levels of the methylation inhibitor SAH, which is attributable to an inhibitory effect of copper on SAHH [62]. The association between oxidative stress and hypomethylation of LINE-1 sequences was reported in bladder cancer patients [63].…”

“…An increase in inflammation in the liver tissue with reduced SAH hydrolase (SAHH) activity, and increased liver SAH, which could also cause global DNA hypomethylation [62], was observed in a mouse model of Wilson's disease. In this model, the methylation level was increased by copper chelation or by treatment with a methyl group donor.…”

Age-dependent stability of nucleoli and global DNA methylation level in spermatocytes of the domestic horse (Equus caballus)

“…The level of methylation was found to decrease with age (Mazin et al 1985;Vanyushin 2005). Other authors confirmed these reports in the case of organs of cattle, mice, and rats (Bird 2002;Medici et al 2013). The importance of DNA methylation for the development of the organism is demonstrated by the fact that mice lacking the DNA methyltransferase gene die within 8 d of fertilization (Sulewska et al 2007;Couldrey and Wells 2013).…”