Polymicrobial sepsis is associated with decreased hepatic oxidative phosphorylation and an altered metabolic profile.
BACKGROUND
Organ failure in sepsis accounts for significant mortality worldwide. Mitochondrial and metabolic responses are central to the overall response of the cell, and thus of the organ and organism. Adaptive responses in metabolism are critical to the recovery at the cellular level. The purpose of these investigations was to test the hypothesis that sepsis is associated with decreased aerobic respiration and significant metabolic changes in the liver.


METHODS
C57BL/6 mice underwent cecal ligation and puncture (CLP) with a 21 gauge needle or an operation without CLP. Mice were euthanized from 0-24 h after the procedure and liver tissue was harvested. Tissue oxygen consumption and mitochondrial complex activity were measured. Global biochemical profiles of 311 metabolites were performed at the 8-h time point (n = 8/group) and analyzed by gas chromatography-mass spectrometry and liquid chromatography tandem mass spectrometry platforms by Metabolon (Durham, North Carolina). The influence of lipopolysaccharide (LPS) on aerobic and anaerobic respiration in primary mouse hepatocytes was also investigated.


RESULTS
CLP in vivo or LPS in vitro resulted in a significant decrease in hepatic oxygen consumption. There was a significant decrease in oxidative phosphorylation measured at 12 h. LPS also resulted in a significant increase in anaerobic respiration in hepatocytes. Interestingly, the metabolomic analysis resulted in a metabolic shift in the liver from carbohydrate-based energy to utilization of fatty acids and amino acids. This included an increase in every tricarboxylic acid cycle intermediate and derivative, suggesting an increased flux into the cycle from fatty acid beta-oxidation and anaplerotic contributions from amino acids.


CONCLUSIONS
Sepsis results in a metabolic response and profile consistent with increased anaerobic respiration, which occurs prior to significant changes in hemodynamics. The metabolic responses of cells and organs may be important adaptive responses to prevent organ failure and death.
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Sean P
SP
Whelan
Evie H
EH
Carchman
Benjamin
B
Kautza
Ibrahim
I
Nassour
Kevin
K
Mollen
Daniel
D
Escobar
Hernando
H
Gomez
Matthew A
MA
Rosengart
Sruti
S
Shiva
Brian S
BS
Zuckerbraun
D000818:Animals; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010085:Oxidative Phosphorylation; D018805:Sepsis / Q000378:metabolism*
Amino Acid; Carbohydrate; Lipopolysaccharide; Metabolomic; fatty acid