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Fenofibrate induces a selective increase of protein-bound homocysteine in rodents: a PPARalpha-mediated effect.

Abstract：

:Elevated levels of plasma homocysteine (Hcy) are associated with increased risk of cardiovascular disease though it is uncertain whether increases in Hcy represent a cause or a consequence of the disease process. Plasma Hcy exists in reduced, free oxidized, and protein-bound forms, that together comprise total Hcy (tHcy). Free reduced Hcy is thought to be the atherogenic, though minor, sub-fraction of tHcy. Recent reports have indicated that fenofibrate and other fibrates are capable of moderately increasing plasma tHcy. As many of the effects of fibrates are known to be mediated by the nuclear receptor PPARalpha, we determined the effect of fenofibrate on tHcy in PPARalpha-deficient mice. We further examined the effect of fenofibrate and fenofibrate plus folate supplementation on total as well as protein-bound Hcy in rats. Fenofibrate significantly increased serum tHcy in wild-type mice but not in PPARalpha deficient mice. In rats, fenofibrate increased serum tHcy by 69%, while the co-administration of folate with fenofibrate increased tHcy by only 7%. In spite of the above increase in tHcy in rats, only the protein-bound fraction of Hcy was increased. In a further study, fenofibrate also induced a significant increase in tHcy, while in spite of this, ex vivo peroxidation of VLDL+LDL was beneficially lowered and the lag time prolonged. In summary, fenofibrate increases serum tHcy in rodents in a PPARalpha-dependent manner. The increase in rats is solely due to protein-bound Hcy as atherogenic, reduced Hcy was unchanged. While awaiting corroboration in human, our results suggest that the extent and mechanism of the increase in total Hcy in patients treated with fenofibrate should not a priori be associated with relevant risk.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Legendre C,Caussé E,Chaput E,Salvayre R,Pineau T,Edgar AD

doi

10.1016/s0006-291x(02)00814-8

subject

Has Abstract

pub_date

2002-08-02 00:00:00

pages

1052-6

issue

eissn

0006-291X

issn

1090-2104

pii

S0006291X02008148

journal_volume

295

pub_type

杂志文章

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Fenofibrate induces a selective increase of protein-bound homocysteine in rodents: a PPARalpha-mediated effect.