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Upregulation of Krebs cycle and anaerobic glycolysis activity early after onset of liver ischemia

by Tom S. Chan, Shamir Cassim, Valérie-Ann Raymond, Sven Gottschalk, Grégory Merlen, Claudia Zwingmann, Pascal Lapierre, Peter Darby, Cyril David Mazer, Marc Bilodeau

The liver is a highly vascularized organ receiving a dual input of oxygenated blood from the hepatic artery and portal vein. The impact of decreased blood flow on glucose metabolism and how hepatocytes could adapt to this restrictive environment are still unclear. Using the left portal vein ligation (LPVL) rat model, we found that cellular injury was delayed after the onset of liver ischemia. We hypothesized that a metabolic adaptation by hepatocytes to maintain energy homeostasis could account for this lag phase. Liver glucose metabolism was characterized by 13C- and 1H-NMR spectroscopy and analysis of high-energy metabolites. ALT levels and caspase 3 activity in LPVL animals remained normal during the first 12 h following surgery (P<0.05). Ischemia rapidly led to decreased intrahepatic tissue oxygen tension and blood flow (P<0.05) and increased expression of Hypoxia-inducible factor 1-alpha. Intrahepatic glucose uptake, ATP/ADP ratio and energy charge level remained stable for up to 12 h after ligation. Entry of glucose in the Krebs cycle was impaired with lowered incorporation of 13C from [U-13C]glucose into glutamate and succinate from 0.25 to 12 h after LPVL. However, total hepatic succinate and glutamate increased 6 and 12 h after ischemia (P<0.05). Glycolysis was initially reduced (P<0.05) but reached maximum 13C-lactate (P<0.001) and 13C-alanine (P<0.01) enrichments 12 h after LPVL. In conclusion, early liver homeostasis stems from an inherent ability of ischemic hepatocytes to metabolically adapt through increased Krebs cycle and glycolysis activity to preserve bioenergetics and cell viability. This metabolic plasticity of hepatocytes could be harnessed to develop novel metabolic strategies to prevent ischemic liver damage.

Authors:   Tom S. Chan; Shamir Cassim; Valérie-Ann Raymond; Sven Gottschalk; Grégory Merlen; Claudia Zwingmann; Pascal Lapierre; Peter Darby; Cyril David Mazer; Marc Bilodeau
Journal:   PLoS ONE
Volume:   13
edition:   6
Year:   2018
Pages:   e0199177
DOI:   10.1371/journal.pone.0199177
Publication date:   14-Jun-2018
Facts, background information, dossiers
  • Expression
  • environment
  • cell viability
  • alanine
More about PLoS ONE
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