Abstract

As the ultimate electron acceptor in oxidative phosphorylation, oxygen plays a critical role in metabolism. When oxygen levels drop, heterodimeric hypoxia-inducible factor (Hif) transcription factors become active and facilitate adaptation to hypoxia. Hif regulation by oxygen requires the protein von Hippel-Lindau (pVhl) and pVhl disruption results in constitutive Hif activation. The liver is a critical organ for metabolic homeostasis, and Vhl inactivation in hepatocytes results in a Hif-dependent shortening in life span. While albumin-Cre;Vhl F/F mice develop hepatic steatosis and impaired fatty acid oxidation, the variable penetrance and unpredictable life expectancy has made the cause of death elusive. Using a system in which Vhl is acutely disrupted and a combination of ex vivo liver perfusion studies and in vivo oxygen measurements, we demonstrate that Vhl is essential for mitochondrial respiration in vivo. Adenovirus-Cre mediated acute Vhl disruption in the liver caused death within days. Deprived of pVhl, livers accumulated tryglicerides and circulating ketone and glucose levels dropped. The phenotype was reminiscent of inborn defects in fatty acid oxidation and of fasted PPARα-deficient mice and while death was unaffected by pharmacologic PPARα activation, it was delayed by glucose administration. Ex vivo liver perfusion analyses and acylcarnitine profiles showed mitochondrial impairment and a profound inhibition of liver ketone and glucose production. By contrast, other mitochondrial functions, such as ureagenesis, were unaffected. Oxygen consumption studies revealed a marked suppression of mitochondrial respiration, which, as determined by magnetic resonance oximetry in live mice, was accompanied by a corresponding increase in liver pO 2. Importantly, simultaneous inactivation of Hif-1Β suppressed liver steatosis and rescued the mice from death. These data demonstrate that constitutive Hif activation in mice is sufficient to suppress mitochondrial respiration in vivo and that no other pathway exists in the liver that can allow oxygen utilization when Hif is active precluding thereby metabolic collapse.

Original languageEnglish (US)
Pages (from-to)2147-2160
Number of pages14
JournalOncogene
Volume30
Issue number18
DOIs
StatePublished - May 5 2011

Fingerprint

Hypoglycemic Agents
Oxygen
Liver
Respiration
Peroxisome Proliferator-Activated Receptors
Ketones
Glucose
Fatty Acids
Perfusion
Hypoxia
Hypoxia-Inducible Factor 1
Proteins
Oximetry
Penetrance
Oxidative Phosphorylation
Fatty Liver
Life Expectancy
Adenoviridae
Oxygen Consumption
Cause of Death

Keywords

  • Hif
  • liver steatosis
  • mitochondrial respiration
  • Vhl

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. / Kucejova, B.; Sunny, N. E.; Nguyen, A. D.; Hallac, R.; Fu, X.; Pẽa-Llopis, S.; Mason, R. P.; Deberardinis, R. J.; Xie, X. J.; Debose-Boyd, R.; Kodibagkar, V. D.; Burgess, S. C.; Brugarolas, J.

In: Oncogene, Vol. 30, No. 18, 05.05.2011, p. 2147-2160.

Research output: Contribution to journalArticle

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AU - Sunny, N. E.

AU - Nguyen, A. D.

AU - Hallac, R.

AU - Fu, X.

AU - Pẽa-Llopis, S.

AU - Mason, R. P.

AU - Deberardinis, R. J.

AU - Xie, X. J.

AU - Debose-Boyd, R.

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AU - Burgess, S. C.

AU - Brugarolas, J.

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