Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle
Copyright policy )Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle
Significance When oxygen availability becomes limited, organs and cells activate the hypoxic response to generate energy. This response releases a large amount of lactate into the circulation as a result of anaerobic glycolysis. However, we found that activating the hypoxic response in the liver by inhibiting the oxygen sensor prolyl hydroxylase domain-containing protein 2 (PHD2) enhances the uptake of lactate for gluconeogenesis, also known as the Cori cycle, and ameliorates lactic acidosis. Our findings suggest that PHD2 serves as a viable drug target for the treatment of life-threatening lactic acidosis, which is frequent complication of severe infectious and ischemic diseases, as well as of biguanide treatment in patients with diabetes with renal failure.
- Keio University Japan
- Japan Science and Technology Agency Japan
- Tokyo Dental College Japan
- Harvard University United States
- Shimadzu Corp. Japan
Blood Glucose, Male, Mice, Knockout, Genotype, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Inbred C57BL, Oxygen, Mice, Liver, Physical Conditioning, Animal, Sepsis, Hepatocytes, Lactates, Animals, Acidosis, Lactic, Blood Gas Analysis, Hypoxia
Blood Glucose, Male, Mice, Knockout, Genotype, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Inbred C57BL, Oxygen, Mice, Liver, Physical Conditioning, Animal, Sepsis, Hepatocytes, Lactates, Animals, Acidosis, Lactic, Blood Gas Analysis, Hypoxia
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