TY - JOUR
T1 - Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model
AU - Arai, K.
AU - Lee, K.
AU - Berthiaume, F.
AU - Tompkins, R. G.
AU - Yarmush, M. L.
N1 - Funding Information:
Abbreviations: FHF, fulminant hepatic failure; BCAA, branched-chain amino acids; TCA, tricarboxylic acid cycle; AST, aspartate transaminase; ALT, alanine transaminase; NADH, nicotinamide adenine dinucleotide; AAA, aromatic amino acids; PEP, phosphoenolpyruvate; ATP, adenosine triphosphate. From the Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and the Shriners Hospitals for Children, Boston, MA. Received October 11, 2000; accepted May 25, 2001. Supported in part by grants from the Shriners Hospitals for Children and the National Institutes of Health grants R01 GM58125 and R01 DK43371. Address reprint requests to: Martin L. Yarmush, M.D., Ph.D., Center for Engineering in Medicine, GRB 1401, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected]; fax: 617-371-4950. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3402-0019$35.00/0 doi:10.1053/jhep.2001.26515
PY - 2001
Y1 - 2001
N2 - A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/vol bovine serum albumin and oxygenated with 95% O2/5% CO2. Control rats were fasted for 36 hours with no other treatment 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 livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to α-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function.
AB - A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/vol bovine serum albumin and oxygenated with 95% O2/5% CO2. Control rats were fasted for 36 hours with no other treatment 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 livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to α-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function.
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U2 - 10.1053/jhep.2001.26515
DO - 10.1053/jhep.2001.26515
M3 - Article
C2 - 11481621
AN - SCOPUS:0034923583
SN - 0270-9139
VL - 34
SP - 360
EP - 371
JO - Hepatology
JF - Hepatology
IS - 2
ER -