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Acute liver injury induces nucleocytoplasmic redistribution of hepatic methionine metabolism enzymes

AuthorsDelgado, Miguel ; Garrido, Francisco ; Pérez-Miguelsanz, Juliana; Pacheco, María ; Partearroyo, Teresa; Pérez-Sala, Dolores ; Pajares, María A.
KeywordsAcute liver injury
Methionine metabolism
Nuclear localization
Subcellular distribution
Epigenetic modification
Glutathione levels
Redox regulation
Methionine adenosyltransferase
Issue Date2014
PublisherMary Ann Liebert
CitationAntioxidants and Redox Signaling 20(16): 2541-2554 (2014)
Abstract[Aims]: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. [Results]: Using the rat model of D-galactosamine intoxication severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine-treatment induced hepatic nuclear accumulation of MATα1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear methionine adenosyltransferase activity. Acetaminophen intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells overexpressing tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and acetaminophen that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased GSH/GSSG ratios and was prevented by N-acetylcysteine and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by N-acetylcysteine in galactosamine-treated cells. [Innovation]: Cytoplasmic and nuclear changes in proteins regulating the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. [Conclusion]: Altogether these results demonstrate galactosamine- and acetaminophen-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of redox-dependent mechanisms in the control of MATα1 subcellular distribution.
Publisher version (URL)http://dx.doi.org/10.1089/ars.2013.5342
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