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

Abstract

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.

Oxaloacetate Protects Rat Liver From Experimental Warm Ischemia/Reperfusion Injury by Improving Cellular Energy Metabolism

“…In the LPVL model, the observed decrease in blood flow induces significant atrophy of the left liver lobes because of cell volume shrinkage and cell death by apoptosis and necrosis . However, there is an early phase where no evidence of cell death can be found despite tissue hypoxia . This early phase is characterized by an increase in glucose metabolism through the glycolytic pathway that allows the maintenance of hepatic bioenergetics for up to 12 hours .…”

“…(12) In this model, hepatocytes could maintain their energy charge (EC) level and prevent cell death for up to 12 hours after ischemia. (12) This early phase, with no evidence of cell death, stemmed from the ability of ischemic hepatocytes to increase glycolysis in order to maintain cell bioenergetics and viability. Because O 2 was limited, anaerobic metabolism was induced to make up for the energy deficit due to the decreased aerobic ATP production, a process known as the Pasteur effect.…”

“…(12) Glutamine was efficiently used to support ATP production and maintain hepatocyte integrity for up to 12 hours. (12) However, this metabolic adaptation was not sufficient to compensate for the energy crisis beyond 12 hours after ischemia. Nonetheless, this observation suggests that promoting mitochondrial metabolism and the production of energetic metabolites by hepatocytes could potentially reduce cell death under conditions of prolonged ischemia.…”

Beneficial effects of the novel marine oxygen carrier M101 during cold preservation of rat and human pancreas

“…Furthermore, this gradient is important for oxygen penetration in tissues, which occurs to a depth of only 5 mm, as a greater amount of oxygen in the solution allows for deeper tissue penetration. In a typical situation, almost no oxygen is in direct contact with the tissue, triggering a reduced respiration rate and glycolysis in the presence of glucose . To survive, cells switch to anaerobic metabolism to produce a small amount of ATP by glycolysis, which leads to poor yields, with only two ATP molecules per glucose vs 36 ATP produced under aerobic condition .…”

“…In a typical situation, almost no oxygen is in direct contact with the tissue, triggering a reduced respiration rate and glycolysis in the presence of glucose. 33,34 To survive, cells switch to anaerobic metabolism to produce a small amount of ATP by glycolysis, which leads to poor yields, with only two ATP molecules per glucose vs 36 ATP produced under aerobic condition. 7 In this study, this phenomenon was demonstrated by a mitochondrial complex 1 activity decrease, leading to low ATP levels in the pancreatic tissue.…”