Agmatine stimulates hepatic fatty acid oxidation: a possible mechanism for up-regulation of ureagenesis.
We demonstrated previously in a liver perfusion system that agmatine increases oxygen consumption as well as the synthesis of N-acetylglutamate and urea by an undefined mechanism. In this study our aim was to identify the mechanism(s) by which agmatine up-regulates ureagenesis. We hypothesized that increased oxygen consumption and N-acetylglutamate and urea synthesis are coupled to agmatine-induced stimulation of mitochondrial fatty acid oxidation. We used 13C-labeled fatty acid as a tracer in either a liver perfusion system or isolated mitochondria to monitor fatty acid oxidation and the incorporation of 13C-labeled acetyl-CoA into ketone bodies, tricarboxylic acid cycle intermediates, amino acids, and N-acetylglutamate. With [U-13C16] palmitate in the perfusate, agmatine significantly increased the output of 13C-labeled beta-hydroxybutyrate, acetoacetate, and CO2, indicating stimulated fatty acid oxidation. The stimulation of [U-13C16]palmitate oxidation was accompanied by greater production of urea and a higher 13C enrichment in glutamate, N-acetylglutamate, and aspartate. These observations suggest that agmatine leads to increased incorporation and flux of 13C-labeled acetyl-CoA in the tricarboxylic acid cycle and to increased utilization of 13C-labeled acetyl-CoA for synthesis of N-acetylglutamate. Experiments with isolated mitochondria and 13C-labeled octanoic acid also demonstrated that agmatine increased synthesis of 13C-labeled beta-hydroxybutyrate, acetoacetate, and N-acetylglutamate. The current data document that agmatine stimulates mitochondrial beta-oxidation and suggest a coupling between the stimulation of hepatic beta-oxidation and up-regulation of ureagenesis. This action of agmatine may be mediated via a second messenger such as cAMP, and the effects on ureagenesis and fatty acid oxidation may occur simultaneously and/or independently.
Nissim
Itzhak
I
Children's Hospital of Philadelphia, Division of Child Development, Rehabilitation Medicine, and Metabolic Disease, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Daikhin
Yevgeny
Y
Nissim
Ilana
I
Luhovyy
Bohdan
B
Horyn
Oksana
O
Wehrli
Suzanne L
SL
Yudkoff
Marc
M
D000244:Adenosine Diphosphate / Q000032:analysis / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000032:analysis / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000376:Agmatine / Q000378:metabolism* / Q000494:pharmacology; D000641:Ammonia / Q000032:analysis / Q000378:metabolism; D000818:Animals; D002247:Carbon Isotopes; D002956:Citrulline / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005971:Glutamates / Q000096:biosynthesis; D007657:Ketone Bodies / Q000096:biosynthesis; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D008954:Models, Biological; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010169:Palmitic Acids / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014508:Urea / Q000032:analysis / Q000378:metabolism*
D002247:Carbon Isotopes; D005227:Fatty Acids; D005971:Glutamates; D007657:Ketone Bodies; D010169:Palmitic Acids; D002956:Citrulline; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000376:Agmatine; D000641:Ammonia; D000255:Adenosine Triphosphate; D014508:Urea