title: Pharmacological PPARα activation markedly alters plasma turnover of the amino acids glycine, serine and arginine in the rat.
abstract: The current study extends previously reported PPARα agonist WY 14,643 (30 µmol/kg/day for 4 weeks) effects on circulating amino acid concentrations in rats fed a 48% saturated fat diet. Steady-state tracer experiments were used to examine in vivo kinetic mechanisms underlying altered plasma serine, glycine and arginine levels. Urinary urea and creatinine excretion were measured to assess whole-body amino acid catabolism. WY 14,643 treated animals demonstrated reduced efficiency to convert food consumed to body weight gain while liver weight was increased compared to controls. WY 14,643 raised total amino acid concentration (38%), largely explained by glycine, serine and threonine increases. 3H-glycine, 14C-serine and 14C-arginine tracer studies revealed elevated rates of appearance (Ra) for glycine (45.5 ± 5.8 versus 17.4 ± 2.7 µmol/kg/min) and serine (21.0 ± 1.4 versus 12.0 ± 1.0) in WY 14,643 versus control. Arginine was substantially decreased (-62%) in plasma with estimated Ra reduced from 3.1 ± 0.3 to 1.2 ± 0.2 µmol/kg/min in control versus WY 14,643. Nitrogen excretion over 24 hours was unaltered. Hepatic arginase activity was substantially decreased by WY 14,643 treatment. In conclusion, PPARα agonism potently alters metabolism of several specific amino acids in the rat. The changes in circulating levels of serine, glycine and arginine reflected altered fluxes into the plasma rather than changes in clearance or catabolism. This suggests that PPARα has an important role in modulating serine, glycine and arginine de novo synthesis.
authors.affiliation: Department of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Ericsson
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Department of Pharmacology, University of New South Wales, Sydney, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: Department of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Göran I
authors.initials: GI
authors.lastname: Hansson
authors.affiliation: Department of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Wallenius
authors.affiliation: Department of Bioscience, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Oakes
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000097:blood*; D001835:Body Weight; D002153:Calorimetry, Indirect; D005998:Glycine / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D009584:Nitrogen / Q000652:urine; D047493:PPAR alpha / Q000819:agonists*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012694:Serine / Q000097:blood*
chemical_list: D047493:PPAR alpha; D011743:Pyrimidines; D012694:Serine; C006253:pirinixic acid; D001120:Arginine; D001119:Arginase; D009584:Nitrogen; D005998:Glycine