33 A study of experimental acetaminophen liver toxicity found tha

33 A study of experimental acetaminophen liver toxicity found that SAM administration restored its mitochondrial and nuclear levels, possibly due to increased expression and activity of methionine adenosyltransferase.34 These results support our findings that the administration of the methyl donor betaine modified SAM levels and consequently the expressions of selected genes. The observed significant 61% reduction of the mean liver Cu level by betaine treatment in control mice and nonsignificant 30% reduction of mean hepatic Cu level in the tx-j mice

(Table 1) are original findings, which could have been influenced by uneven hepatic Cu distribution in ACP-196 purchase the liver.35 Potentially, betaine could reduce Cu levels by modification of the expressions of genes for Cu chaperones or cellular transport. Ultimately, only long-term studies on betaine treatment for tx-j mice may clarify this issue. Currently, the molecular mechanisms linking Cu and gene expression are unknown but it seems likely that methylation plays an important role. Reduced global methylation in the untreated tx-j

mice could relate to increased inflammation, which others have associated with increased demand for gene methylation resulting from increased cell division and DNA.16, 17 Consequently, WD may be associated with increased demand for methyl groups as result of both an increase of the methylation inhibitor SAH and increased inflammation. Although the associations of Cu-mediated SAHH inhibition with SAH accumulation and reduced Dnmt3b

transcripts were consistent 26s Proteasome structure with global DNA hypomethylation in tx-j mouse livers, the relationship between DNA hypomethylation and down-regulation of the expressions of genes representative of ER stress, lipogenesis, and fatty acid oxidation in untreated tx-j mice is less clear. Similar to our data, others described down-regulation of gene transcripts representative of lipid metabolism in the Atp7b−/− knockout mouse at 6 weeks of age, prior to development of histological damage.36 However, this study did not find any changes in Sahh and Dnmt1 expressions, whereas Dnmt3a, Dnmt3b, and potential changes in lipid metabolism in response to Cu chelation were not measured. In the present selleck products study, the hypothesis that the observed changes in gene transcript levels with PCA treatment are due to changes in methylation is supported by observations that both PCA and betaine treatments were associated with significant increases in global DNA methylation and by the positive correlations between Dnmt3b transcripts and global DNA methylation and transcripts of genes representative of ER stress, lipogenesis, and fatty acid oxidation. There are potentially other mechanisms involved in the gene expression response to Cu accumulation and PCA.

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