Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model

A better understanding of the hepatic metabolic pathways affected by fulmin ant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver s ystem in combination with a mass-balance model of hepatic intermediary meta bolism to generate a comprehensive map of metabolic alterations in the live r in FHF. To induce FHF, rats were fasted for 36 hours, during which they r eceived 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal esse ntial medium containing 3% wt/vol bovine serum albumin and oxygenated with 95% O-2/5% CO2- Control rats were fasted for 36 hours with no other treatme nt before perfusion. FHF rat livers exhibited reduced amino acid uptake, a switch from gluconeogenesis to glycolysis, and a decrease in urea synthesis , but no change in ammonia consumption compared with normal fasted rat live rs. Mass-balance analysis showed that hepatic glucose synthesis was inhibit ed as a result of a reduction in amino acid entry into the tricarboxylic ac id cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synth esis by conversion of exogenous arginine to ornithine was unchanged. Ammoni a removal was quantitatively maintained by glutamine synthesis from glutama te and a decrease in the conversion of glutamate to a-ketoglutarate. Mass-b alance analysis of hepatic metabolism will be useful in characterizing chan ges during FHF, and in elucidating the effects of nutritional supplements a nd other treatments on hepatic function.