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Biochim Biophys Acta. 2016 Sep;1862(9):1495-503. doi: 10.1016/j.bbadis.2016.05.011. Epub 2016 May 20.

Impact of Dyrk1A level on alcohol metabolism.

Author information

1
Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France.
2
Univ René Descartes, Sorbonne Paris Cité, Unité de Pharmacologie, Toxicologie et Signalisation Cellulaire, INSERM UMR-S 1124, Paris, France.
3
AP-HP, Hôpital Européen Georges Pompidou, Service de Biochimie, 75015 Paris, France.
4
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
5
Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France. Electronic address: janel@univ-paris-diderot.fr.

Abstract

Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level.

KEYWORDS:

Alcohol dehydrogenase; Ethanol; Hyperhomocysteinemia; Liver; Mice

PMID:
27216978
DOI:
10.1016/j.bbadis.2016.05.011
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