Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran

Recently two novel enzymes were identified in the outer mitochondrial membrane, mARC1 and mARC2. These molybdenum containing enzymes can reduce a variety of N-hydroxylated compounds, such as N-hydroxy-guanidines and sulfohydroxamic acids, as well as convert nitrite into nitric oxide (NO). However, t...

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Main Authors:	Neve, Etienne P. A., Köfeler, Harald, Hendriks, Delilah F. G., Nordling, Åsa, Gogvadze, Vladimir, Mkrtchian, Souren, Näslund, Erik, Ingelman-Sundberg, Magnus
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574727/

id	pubmed-4574727
recordtype	oai_dc
spelling	pubmed-45747272015-09-25 Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran Neve, Etienne P. A. Köfeler, Harald Hendriks, Delilah F. G. Nordling, Åsa Gogvadze, Vladimir Mkrtchian, Souren Näslund, Erik Ingelman-Sundberg, Magnus Research Article Recently two novel enzymes were identified in the outer mitochondrial membrane, mARC1 and mARC2. These molybdenum containing enzymes can reduce a variety of N-hydroxylated compounds, such as N-hydroxy-guanidines and sulfohydroxamic acids, as well as convert nitrite into nitric oxide (NO). However, their endogenous functions remain unknown. Here we demonstrate a specific developmental pattern of expression of these enzymes. mARC1, but not mARC2, was found to be expressed in fetal human liver, whereas both, in particular mARC2, are abundant in adult liver and also expressed in omental and subcutaneous fat. Caloric diet restriction of obese patients caused a decreased expression of mARC2 in liver, similar to that seen in the livers of starved rats. Knock down of mARC2 expression by siRNA in murine adipocytes had statistically significant effect on the level of diglycerides and on the fatty acid composition of some triglycerides, concomitantly a clear trend toward the reduced formation of most of triglyceride and phospholipid species was observed. The involvement of mARC2 in the metabolism of the hepatotoxic drug ximelagatran was evaluated in hepatocytes and adipocytes. Ximelagatran was shown to cause oxidative stress and knock down of mARC2 in adipocytes prevented ximelagatran induced inhibition of mitochondrial respiration. In conclusion, our data indicate that mARC1 and mARC2 have different developmental expression profiles, and that mARC2 is involved in lipogenesis, is regulated by nutritional status and responsible for activation of ximelagatran into a mitotoxic metabolite(s). Public Library of Science 2015-09-17 /pmc/articles/PMC4574727/ /pubmed/26378779 http://dx.doi.org/10.1371/journal.pone.0138487 Text en © 2015 Neve et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Neve, Etienne P. A. Köfeler, Harald Hendriks, Delilah F. G. Nordling, Åsa Gogvadze, Vladimir Mkrtchian, Souren Näslund, Erik Ingelman-Sundberg, Magnus
spellingShingle	Neve, Etienne P. A. Köfeler, Harald Hendriks, Delilah F. G. Nordling, Åsa Gogvadze, Vladimir Mkrtchian, Souren Näslund, Erik Ingelman-Sundberg, Magnus Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran
author_facet	Neve, Etienne P. A. Köfeler, Harald Hendriks, Delilah F. G. Nordling, Åsa Gogvadze, Vladimir Mkrtchian, Souren Näslund, Erik Ingelman-Sundberg, Magnus
author_sort	Neve, Etienne P. A.
title	Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran
title_short	Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran
title_full	Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran
title_fullStr	Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran
title_full_unstemmed	Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran
title_sort	expression and function of marc: roles in lipogenesis and metabolic activation of ximelagatran
description	Recently two novel enzymes were identified in the outer mitochondrial membrane, mARC1 and mARC2. These molybdenum containing enzymes can reduce a variety of N-hydroxylated compounds, such as N-hydroxy-guanidines and sulfohydroxamic acids, as well as convert nitrite into nitric oxide (NO). However, their endogenous functions remain unknown. Here we demonstrate a specific developmental pattern of expression of these enzymes. mARC1, but not mARC2, was found to be expressed in fetal human liver, whereas both, in particular mARC2, are abundant in adult liver and also expressed in omental and subcutaneous fat. Caloric diet restriction of obese patients caused a decreased expression of mARC2 in liver, similar to that seen in the livers of starved rats. Knock down of mARC2 expression by siRNA in murine adipocytes had statistically significant effect on the level of diglycerides and on the fatty acid composition of some triglycerides, concomitantly a clear trend toward the reduced formation of most of triglyceride and phospholipid species was observed. The involvement of mARC2 in the metabolism of the hepatotoxic drug ximelagatran was evaluated in hepatocytes and adipocytes. Ximelagatran was shown to cause oxidative stress and knock down of mARC2 in adipocytes prevented ximelagatran induced inhibition of mitochondrial respiration. In conclusion, our data indicate that mARC1 and mARC2 have different developmental expression profiles, and that mARC2 is involved in lipogenesis, is regulated by nutritional status and responsible for activation of ximelagatran into a mitotoxic metabolite(s).
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574727/
_version_	1613477135275524096

Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran

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