Release of the mitochondrial enzyme carbamoyl phosphate synthase under septic conditions

Shock. 2005 Jun;23(6):533-8.

Abstract

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.

MeSH terms

  • Animals
  • Arginine / metabolism
  • Bilirubin / metabolism
  • Blotting, Western
  • Carbamoyl-Phosphate Synthase (Ammonia) / chemistry*
  • Carbamoyl-Phosphate Synthase (Ammonia) / metabolism
  • Electrophoresis, Gel, Two-Dimensional
  • Endotoxins / metabolism
  • Humans
  • Immunoassay
  • Intestine, Small / pathology
  • Kinetics
  • Lipopolysaccharides / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Mass Spectrometry
  • Mitochondria / enzymology*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Papio
  • Peptides / chemistry
  • Protein Structure, Tertiary
  • Proteomics
  • Sepsis / enzymology*
  • Sepsis / metabolism
  • Subcellular Fractions / metabolism
  • Submitochondrial Particles / metabolism
  • Time Factors
  • Urea / metabolism

Substances

  • Endotoxins
  • Lipopolysaccharides
  • Peptides
  • Urea
  • Arginine
  • Carbamoyl-Phosphate Synthase (Ammonia)
  • Bilirubin