A role for PPARa in the regulation of arginine metabolismand nitric oxide synthesis
Résumé
The pleiotropic effects of PPARa may includethe regulation of amino acid metabolism. Nitric oxide (NO)is a key player in vascular homeostasis. NO synthesis maybe jeopardized by a differential channeling of argininetoward urea (via arginase) versus NO (via NO synthase,NOS). This was studied in wild-type (WT) and PPARa-null(KO) mice fed diets containing either saturated fatty acids(COCO diet) or 18:3 n-3 (LIN diet). Metabolic markers ofarginine metabolism were assayed in urine and plasma.mRNA levels of arginases and NOS were determined inliver. Whole-body NO synthesis and the conversion ofsystemic arginine into urea were assessed by using 15N2-guanido-arginine and measuring urinary 15NO3 and [15N]-urea. PPARa deficiency resulted in a markedly lowerwhole-body NO synthesis, whereas the conversion of systemicarginine into urea remained unaffected. PPARadeficiency also increased plasma arginine and decreasedcitrulline concentration in plasma. These changes could notbe ascribed to a direct effect on hepatic target genes, sinceNOS mRNA levels were unaffected, and arginase mRNAlevels decreased in KO mice. Despite the low level in thediet, the nature of the fatty acids modulated some effects ofPPARa deficiency, including plasma arginine and urea,which increased more in KO mice fed the LIN diet than inthose fed the COCO diet. In conclusion, PPARa is largelyinvolved in normal whole-body NO synthesis. This warrantsfurther study on the potential of PPARa activation tomaintain NO synthesis in the initiation of the metabolicsyndrome.