Switching Off PHD2 Helps Mice Survive Lactic Acidosis

Inhibiting the oxygen sensor PHD2 could be one way to treat lactic acidosis, according to a study in mice.

AsianScientist (Sep. 17, 2015) – Researchers from the Keio University School of Medicine have discovered a hypoxia regulating factor that is able to reduce the blood lactate level and improve survival in lactic acidosis. Their findings have been published in the Proceedings of the Academy of Science.

After vigorous activity (i.e. exercise) that uses up our normal energy stores and when our cell’s oxygen supply is limited (hypoxia), lactic acid is released into our muscle to act as a backup source of energy. A build-up of lactic acid will decrease the pH of the blood, which in serious cases may lead to organ failure and septic shock.

In the present study, Assistant Professor Yoji Andrew Minamishima and his team from Keio University may have found a way to combat lactic acidosis. They inactivated a gene called Phd2 in the liver, causing the built up lactate to be metabolized into glucose (gluconeogenesis), a process which could increase the likelihood of survival in the event of life-threatening lactic acidosis.

“We hypothesize that the PHD2-blockade enhances lactate clearance,” Minamishia told Asian Scientist Magazine. “Since the liver is known to incorporate blood lactate from gluconeogenesis via the Cori cycle, we thought that PHD2-blocade in the liver would contribute to decreasing blood lactate level.”

The Cori cycle, also known as the lactic acid cycle, is the metabolic pathway where lactate that is produced through anaerobic glycolysis is converted into glucose in the liver, and is then returns to the muscle where it can be metabolized into lactate.

How PHD2-inhibition can reduce lactic acidosis. Credit: Yoji Andrew Minamishima/Keio University.
How PHD2-inhibition can reduce lactic acidosis. Credit: Yoji Andrew Minamishima/Keio University.

Minamishima suggests that PHD2 could potentially be made into a viable new drug target for life threatening cases of lactic acidosis by activating the Cori cycle and assist in ameliorating such cases alongside other potential drugs that are entering the market.

“There is small compound called FG-4592 from FibroGen which has been undergoing a Phase III clinical trial for the treatment of renal anemia. As an inhibitor of hypoxida-inducing factor, it could potentially also be used to treat lactic acidosis,” he explained.

However, Minamishima cautions against inhibiting PHD2 systematically for long periods of time, which could lead to an increased concentration of hemoglobin in the blood (polycytermia) and heart failure.

In addition to his current research on PHD2, Minamishima is potentially interested in how lactic acidosis is frequently complicated with septic shock and ischemic diseases.

The article can be found at: Suhara et al. (2015) Inhibition of the Oxygen Sensor PHD2 in the Liver Improves Survival in Lactic Acidosis by Activating the Cori Cycle.

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Copyright: Asian Scientist Magazine; Photo: Shutterstock.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Jeremy is a finishing his PhD in regenerative biology at the Australian Regenerative Medicine Institute (ARMI), Monash University in Melbourne, Australia. In his spare time, he enjoys cooking, traveling, science jokes and teaching Australians how to pronounce his last name.

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