Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle

Proceedings of the National Academy of Sciences of the United States of America
Tomohiro SuharaYoji Andrew Minamishima

Abstract

Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo (13)C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from (13)C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of la...Continue Reading

References

Jan 1, 1969·Advances in Enzyme Regulation·P FeligG F Cahill
Feb 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·V H HaaseR Jaenisch
Dec 6, 2005·Journal of the American College of Cardiology·Masakuni KidoPatricia A Thistlethwaite
Jun 8, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Oxana BaranovaJuan C Chavez
Jul 10, 2007·Intensive Care Medicine·Jan Bakker, Tim C Jansen
May 24, 2008·Molecular Cell·William G Kaelin, Peter J Ratcliffe
Dec 17, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Tsunehiro ShintaniMakoto Suematsu
Sep 2, 2009·Molecular and Cellular Biology·Yoji Andrew MinamishimaWilliam G Kaelin
Nov 26, 2009·Proceedings of the National Academy of Sciences of the United States of America·W M BernhardtK-U Eckardt
Feb 25, 2010·JAMA : the Journal of the American Medical Association·Alan E JonesUNKNOWN Emergency Medicine Shock Research Network (EMShockNet) Investigators
May 14, 2010·American Journal of Respiratory and Critical Care Medicine·Tim C JansenUNKNOWN LACTATE study group
Jul 24, 2010·Science·Yoji Andrew Minamishima, William G Kaelin
Aug 13, 2011·The New England Journal of Medicine·Gregg L Semenza
Dec 15, 2012·World Journal of Gastroenterology : WJG·Sumera KarimPatricia F Lalor
Mar 20, 2013·Molecular Aspects of Medicine·Andrew P Halestrap
Jun 7, 2013·Molecular Cancer Research : MCR·Yan BaoYoji Andrew Minamishima
Aug 30, 2013·The New England Journal of Medicine·Derek C Angus, Tom van der Poll
Apr 3, 2014·Comprehensive Physiology·Liangyou Rui
Aug 5, 2014·Biochemical and Biophysical Research Communications·Daisuke KikuchiKoh Nakayama
Dec 24, 2014·JAMA : the Journal of the American Medical Association·Silvio E InzucchiDarren K McGuire

❮ Previous
Next ❯

Citations

Jan 23, 2016·Molecular Aspects of Medicine·Mun Chiang ChanPeter J Ratcliffe
May 10, 2017·Proceedings of the National Academy of Sciences of the United States of America·Michele FerrariWarren M Zapol
Dec 14, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kentaro TojoTakahisa Goto
Mar 31, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Beibei LuoYi-Ping Hu
Nov 1, 2016·Molecular and Cellular Biology·Annemarie GuentschDörthe M Katschinski
Jun 14, 2017·Molecular and Cellular Biology·Tomoko Oyaizu-ToramaruYoji Andrew Minamishima
Aug 15, 2017·The Journal of Clinical Investigation·Pranvera SadikuSarah R Walmsley
May 27, 2020·Current Opinion in Nephrology and Hypertension·Yu KurataMasaomi Nangaku
Jan 7, 2020·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Yoji Andrew Minamishima
Jun 26, 2018·Frontiers in Oncology·Florinda Meléndez-RodríguezJulian Aragones
Sep 13, 2018·Scientific Reports·Jenni MäättäPeppi Koivunen
Apr 1, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kentaro TojoTakahisa Goto
Nov 1, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ling TangYang Liu

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.