A role for PPARα in the regulation of arginine metabolism and nitric oxide synthesis

Amino Acids. 2011 Oct;41(4):969-79. doi: 10.1007/s00726-010-0797-7. Epub 2010 Nov 10.


The pleiotropic effects of PPARα may include the regulation of amino acid metabolism. Nitric oxide (NO) is a key player in vascular homeostasis. NO synthesis may be jeopardized by a differential channeling of arginine toward urea (via arginase) versus NO (via NO synthase, NOS). This was studied in wild-type (WT) and PPARα-null (KO) mice fed diets containing either saturated fatty acids (COCO diet) or 18:3 n-3 (LIN diet). Metabolic markers of arginine metabolism were assayed in urine and plasma. mRNA levels of arginases and NOS were determined in liver. Whole-body NO synthesis and the conversion of systemic arginine into urea were assessed by using (15)N(2)-guanido-arginine and measuring urinary (15)NO(3) and [(15)N]-urea. PPARα deficiency resulted in a markedly lower whole-body NO synthesis, whereas the conversion of systemic arginine into urea remained unaffected. PPARα deficiency also increased plasma arginine and decreased citrulline concentration in plasma. These changes could not be ascribed to a direct effect on hepatic target genes, since NOS mRNA levels were unaffected, and arginase mRNA levels decreased in KO mice. Despite the low level in the diet, the nature of the fatty acids modulated some effects of PPARα deficiency, including plasma arginine and urea, which increased more in KO mice fed the LIN diet than in those fed the COCO diet. In conclusion, PPARα is largely involved in normal whole-body NO synthesis. This warrants further study on the potential of PPARα activation to maintain NO synthesis in the initiation of the metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / blood
  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Arginine / analogs & derivatives
  • Arginine / blood
  • Arginine / metabolism*
  • Arginine / urine
  • Biomarkers / metabolism
  • Fatty Acids, Omega-3 / pharmacology
  • Gene Expression Regulation, Enzymologic
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Urea / metabolism
  • alpha-Linolenic Acid / pharmacology


  • Amino Acids
  • Biomarkers
  • Fatty Acids, Omega-3
  • PPAR alpha
  • guanidinoarginine
  • alpha-Linolenic Acid
  • Nitric Oxide
  • Urea
  • Arginine
  • Nitric Oxide Synthase
  • Arginase