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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0298v1 204/2/191    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Beltowski, J. Articles by Jakubowski, H. PubMed PubMed Citation Articles by Beltowski, J. Articles by Jakubowski, H.

Jerzy Betowski, Grayna Wójcicka

Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland
¹ Department of Microbiology and Molecular Genetics, New Jersey Medical School, International Center for Public Health, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07101, USA
² Department of Biochemistry and Biotechnology, University of Life Sciences, 60-637 Poznañ, Poland

(Correspondence should be addressed to J Betowski; Email: jerzy.beltowski{at}am.lublin.pl)

The adipose tissue hormone leptin and homocysteine (Hcy)-thiolactone are linked to the pathogenesis of atherosclerosis through their interactions with the anti-atherogenic enzyme paraoxonase 1 that has the ability to hydrolyze Hcy-thiolactone and minimizes protein N-homocysteinylation. Here we examined the relationships between hyperleptinemia, Hcy-thiolactonase, and protein N-homocysteinylation in rats. Hyperleptinemia was induced in adult rats by administration of leptin for 7 days (0.25 mg/kg twice daily s.c). We found that serum Hcy-thiolactonase was lower in hyperleptinemic than in control animals (–41.0%, P<0.001). Leptin administration increased the level of N-linked Hcy in plasma proteins (+92.9%, P<0.01), but had no effect on plasma total Hcy. These effects were not reproduced by pair-feeding. We also found that the synthetic liver X receptor (LXR) agonist, T0901317 (1 mg/kg per day) normalized Hcy-thiolactonase and protein N-homocysteinylation levels in leptin-treated rats. However, leptin-induced increase in plasma isoprostane levels (a marker of oxidative stress) was not normalized by T0901317. The NADPH oxidase inhibitor apocynin prevented leptin-induced increase in isoprostane levels but did not normalize Hcy-thiolactonase and protein N-homocysteinylation levels. These results suggest that the decreased capacity to metabolize Hcy-thiolactone and concomitant increase in protein N-homocysteinylation contribute to pro-atherogenic effect of chronic hyperleptinemia, independently of oxidative stress. LXR agonists normalize Hcy-thiolactonase levels and decrease protein N-homocysteinylation, especially under conditions associated with excess leptin such as metabolic syndrome.