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 C-13-labeled fatty acid as a tracer in either a liver perfusion system or isolated mitochondria to monitor fatty acid oxidation and the incorporation of C-13- labeled acetyl- CoA into ketone bodies, tricarboxylic acid cycle intermediates, amino acids, and N- acetylglutamate. With [U-C-13(16)] palmitate in the perfusate, agmatine significantly increased the output of C-13-labeled beta-hydroxybutyrate, acetoacetate, and CO2, indicating stimulated fatty acid oxidation. The stimulation of [U-C-13(16)] palmitate oxidation was accompanied by greater production of urea and a higher C-13 enrichment in glutamate, N- acetylglutamate, and aspartate. These observations suggest that agmatine leads to increased incorporation and flux of C-13- labeled acetyl- CoA in the tricarboxylic acid cycle and to increased utilization of C-13- labeled acetyl- CoA for synthesis of N- acetylglutamate. Experiments with isolated mitochondria and C-13 -labeled octanoic acid also demonstrated that agmatine increased synthesis of C-13- labeled beta- hydroxybutyrate, acetoacetate, and N- acetyl-glutamate. 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.