title: Evolution of intrahepatic carbon, nitrogen, and energy metabolism in a D-galactosamine-induced rat liver failure model.
abstract: A clearer picture of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and nonsurgical therapies for FHF. We characterized the evolution of hepatic metabolism in a rat model of FHF using an isolated perfused liver system together with a mass-balance model of intermediary metabolism. Principal component analysis (PCA) was used to identify potential new sensitive markers for FHF. To induce FHF, rats were given two D-galactosamine injections under fasting conditions. Controls were fasted only. Livers were harvested 1, 4, 8, and 12 h later and perfused with Eagle minimal essential medium supplemented with amino acids and bovine serum albumin, and equilibrated with 95% O2/5% CO2. At the 1 h time point, lactate release increased concomitant with a decrease in gluconeogenesis, TCA cycle and mitochondrial electron transport fluxes. At 4 h, amino acid metabolism and urea cycle fluxes were significantly depressed. By 8 h, gluconeogenesis had switched to glycolysis. By 12 h, amino acid metabolism was broadly inhibited, and there was a net release of many amino acids. Mass-balance analysis shows that the main source of ATP production in the FHF liver gradually changed from mitochondrial oxidative phosphorylation to glycolysis. PCA suggests that a linear combination of glucose, lactate, and glutamine concentrations in arterial plasma is a sensitive marker for FHF. We conclude that D-galactosamine causes early mitochondrial dysfunction while glycolytic ATP synthesis remains functional. Markers that are indirectly linked to these pathways may be used to evaluate the progression of FHF.
authors.affiliation: Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom Street, Boston, MA 02114, USA.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Scott
authors.initials: S
authors.lastname: Banta
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: D000818:Animals; D015415:Biomarkers; D002244:Carbon / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D005688:Galactosamine / Q000633:toxicity*; D066298:In Vitro Techniques; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009584:Nitrogen / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D002244:Carbon; D005688:Galactosamine; D009584:Nitrogen