Modulation of paraoxonase 1 and protein N-homocysteinylation by leptin and the synthetic liver X receptor agonist T0901317 in the rat

被引:18
作者
Beltowski, Jerzy [1 ]
Wojcicka, Grazyna [1 ]
Jakubowski, Hieronim [2 ,3 ]
机构
[1] Med Univ, Dept Pathophysiol, PL-20090 Lublin, Poland
[2] Univ Med & Dent New Jersey, Int Ctr Publ Hlth, New Jersey Med Sch, Dept Microbiol & Mol Genet, Newark, NJ 07101 USA
[3] Univ Life Sci, Dept Biochem & Biotechnol, PL-60637 Poznan, Poland
关键词
SERUM PARAOXONASE; ENDOTHELIAL DYSFUNCTION; THIOLACTONASE ACTIVITY; DENSITY-LIPOPROTEINS; OXIDATIVE STRESS; BIOLOGICAL ROLE; PLASMA; ATHEROSCLEROSIS; MECHANISM; DISEASE;
D O I
10.1677/JOE-09-0298
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. Journal of Endocrinology (2010) 204, 191-198
引用
收藏
页码:191 / 198
页数:8
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