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 β-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 β-hydroxybutyrate, acetoacetate, and N-acetylglutamate. The current data document that agmatine stimulates mitochondrial β-oxidation and suggest a coupling between the stimulation of hepatic β-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.