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

Neve EP, Köfeler H, Hendriks DF, Nordling Å, Gogvadze V, Mkrtchian S, Näslund E, Ingelman-Sundberg M - PLoS ONE (2015)

Bottom Line: 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.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.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).

View Article: PubMed Central - PubMed

Affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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).

No MeSH data available.


Related in: MedlinePlus

Expression of mARC1 and mARC2 in human adult and fetal liver.A. mARC1 and mARC2 gene expression in human fetal (n = 14) and adult (n = 88) liver samples was determined by microarray analysis and presented as background corrected probe intensities. ***p<0.001. B. mARC1 and mARC2 protein expression in 8 fetal and 9 adult livers. Equal amounts of protein were analyzed for the expression of mARC1 (upper panel), mARC2 (middle panel). Specific bands for both proteins were identified at the level of approximately 35 kDa, an apparent molecular mass of mARC1 and 2. ERp29 was used as a loading control (lower panel).
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pone.0138487.g001: Expression of mARC1 and mARC2 in human adult and fetal liver.A. mARC1 and mARC2 gene expression in human fetal (n = 14) and adult (n = 88) liver samples was determined by microarray analysis and presented as background corrected probe intensities. ***p<0.001. B. mARC1 and mARC2 protein expression in 8 fetal and 9 adult livers. Equal amounts of protein were analyzed for the expression of mARC1 (upper panel), mARC2 (middle panel). Specific bands for both proteins were identified at the level of approximately 35 kDa, an apparent molecular mass of mARC1 and 2. ERp29 was used as a loading control (lower panel).

Mentions: In order to examine the developmental pattern of the expression of mARC1 and mARC2, the mRNA levels of both genes were analyzed in 88 adult and 14 fetal human livers (S1 Fig, Fig 1A). The mARC1 mRNA expression levels appear not to be significantly different between the fetal and the adult tissues, although the variability is larger in the adult livers compared to the fetal ones. In contrast, mARC2 is only expressed in the adult livers, only very low levels are observed in the fetal tissues, suggesting that the expression of mARC2 is developmentally regulated while the expression of mARC1 is not.


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

Neve EP, Köfeler H, Hendriks DF, Nordling Å, Gogvadze V, Mkrtchian S, Näslund E, Ingelman-Sundberg M - PLoS ONE (2015)

Expression of mARC1 and mARC2 in human adult and fetal liver.A. mARC1 and mARC2 gene expression in human fetal (n = 14) and adult (n = 88) liver samples was determined by microarray analysis and presented as background corrected probe intensities. ***p<0.001. B. mARC1 and mARC2 protein expression in 8 fetal and 9 adult livers. Equal amounts of protein were analyzed for the expression of mARC1 (upper panel), mARC2 (middle panel). Specific bands for both proteins were identified at the level of approximately 35 kDa, an apparent molecular mass of mARC1 and 2. ERp29 was used as a loading control (lower panel).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4574727&req=5

pone.0138487.g001: Expression of mARC1 and mARC2 in human adult and fetal liver.A. mARC1 and mARC2 gene expression in human fetal (n = 14) and adult (n = 88) liver samples was determined by microarray analysis and presented as background corrected probe intensities. ***p<0.001. B. mARC1 and mARC2 protein expression in 8 fetal and 9 adult livers. Equal amounts of protein were analyzed for the expression of mARC1 (upper panel), mARC2 (middle panel). Specific bands for both proteins were identified at the level of approximately 35 kDa, an apparent molecular mass of mARC1 and 2. ERp29 was used as a loading control (lower panel).
Mentions: In order to examine the developmental pattern of the expression of mARC1 and mARC2, the mRNA levels of both genes were analyzed in 88 adult and 14 fetal human livers (S1 Fig, Fig 1A). The mARC1 mRNA expression levels appear not to be significantly different between the fetal and the adult tissues, although the variability is larger in the adult livers compared to the fetal ones. In contrast, mARC2 is only expressed in the adult livers, only very low levels are observed in the fetal tissues, suggesting that the expression of mARC2 is developmentally regulated while the expression of mARC1 is not.

Bottom Line: 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.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.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).

View Article: PubMed Central - PubMed

Affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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).

No MeSH data available.


Related in: MedlinePlus