Modulation of paraoxonase 1 and protein N-homocysteinylation by leptin and the synthetic liver X receptor agonist T0901317 in the rat.
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.
Beltowski
Jerzy
J
Department of Pathophysiology, Medical University, 20-090 Lublin, Poland. jerzy.beltowski@am.lublin.pl
Wójcicka
Grazyna
G
Jakubowski
Hieronim
H
D000098:Acetophenones; D000818:Animals; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000098:Acetophenones; D043303:Aryldialkylphosphatase; D001798:Blood Proteins; D006710:Homocysteine; D006845:Hydrocarbons, Fluorinated; D020738:Leptin; D000071518:Liver X Receptors; D019255:NADPH Oxidases; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C056165:acetovanillone; C007957:homocysteine thiolactone