Release of the mitochondrial enzyme carbamoyl phosphate synthase under septic conditions.
To identify sepsis-related dysregulations of protein expression in the liver, we used a baboon model of acute endotoxemia and performed comparative proteome analysis. Treatment with lipopolysaccharide (LPS) was followed by an early but long-lasting (5-48 h) generation of N-terminal fragments of carbamoyl phosphate synthase-1 (CPS-1), an abundant enzyme of the hepatic urea cycle, which is normally located in the mitochondrial matrix. In addition, we developed a new sandwich immunoassay to determine circulating CPS-1 in human and baboons. We found CPS-1 to be induced by LPS and to be released into the circulation of healthy humans and baboons as early as 4 to 5 h after stimulation. Similarly, CPS-1 levels increased after injection of gram-positive bacteria in another baboon model. Enhanced CPS-1 levels were also detected in serum of patients with sepsis. Our data demonstrate fragmentation of CPS-1 in the liver and early increase in circulating CPS-1 levels under septic conditions. We suggest that circulating CPS-1 might serve as a novel serum marker indicating mitochondrial impairment of the liver and/or the small intestine in critically ill patients.
Struck
Joachim
J
Department of Research, B.R.A.H.M.S Aktiengesellschaft, D-16761 Hennigsdorf, Germany. j.struck@brahms.de
Uhlein
Monika
M
Morgenthaler
Nils G
NG
Fürst
Walter
W
Höflich
Conny
C
Bahrami
Soheyl
S
Bergmann
Andreas
A
Volk
Hans-Dieter
HD
Redl
Heinz
H
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D015153:Blotting, Western; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000737:chemistry* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004731:Endotoxins / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D007421:Intestine, Small / Q000473:pathology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D013058:Mass Spectrometry; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D010215:Papio; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D040901:Proteomics; D018805:Sepsis / Q000201:enzymology* / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013367:Submitochondrial Particles / Q000378:metabolism; D013997:Time Factors; D014508:Urea / Q000378:metabolism
D004731:Endotoxins; D008070:Lipopolysaccharides; D010455:Peptides; D014508:Urea; D001120:Arginine; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D001663:Bilirubin