Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death

B Kucejova; N E Sunny; A D Nguyen; R Hallac; X Fu; S Peña-Llopis; R P Mason; R J Deberardinis; Xian Jin Xie; R Debose-Boyd; V D Kodibagkar; S C Burgess; J Brugarolas

doi:10.1038/onc.2010.587

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Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death

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Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death

B Kucejova, N E Sunny, A D Nguyen, R Hallac, X Fu, S Peña-Llopis, R P Mason, R J Deberardinis, Xian Jin Xie, R Debose-Boyd, …

Oncogene, Vol.30(18), pp.2147-2160

05/05/2011

DOI: 10.1038/onc.2010.587

PMCID: PMC3135264

PMID: 21217781

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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.

Signal Transduction

Liver - metabolism

Von Hippel-Lindau Tumor Suppressor Protein - physiology

Hypoglycemia - pathology

Hypoglycemia - metabolism

Reverse Transcriptase Polymerase Chain Reaction

Oxygen - metabolism

Hypoxia - metabolism

Animals

Ketones - blood

Mice

Von Hippel-Lindau Tumor Suppressor Protein - genetics

Gluconeogenesis

Details

Title: Subtitle: Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death
Creators: B Kucejova - Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
N E Sunny
A D Nguyen
R Hallac
X Fu
S Peña-Llopis
R P Mason
R J Deberardinis
Xian Jin Xie - University of Iowa, Dental Research
R Debose-Boyd
V D Kodibagkar
S C Burgess
J Brugarolas
Resource Type: Journal article
Publication Details: Oncogene, Vol.30(18), pp.2147-2160
DOI: 10.1038/onc.2010.587
PMID: 21217781
PMCID: PMC3135264
NLM abbreviation: Oncogene
ISSN: 0950-9232
eISSN: 1476-5594
Publisher: England
Grant note: K08 NS051843-05 / NINDS NIH HHS R01 CA129387-01A2 / NCI NIH HHS U24 CA126608-02 / NCI NIH HHS R01 CA139043 / NCI NIH HHS K08 NS051843 / NINDS NIH HHS R01 CA129387 / NCI NIH HHS R21 CA132096 / NCI NIH HHS U24 CA126608-01 / NCI NIH HHS R01 CA129387-04 / NCI NIH HHS R01 DK078184-04 / NIDDK NIH HHS K08 NS051843-03 / NINDS NIH HHS P41 RR002584 / NCRR NIH HHS U24 CA126608-05 / NCI NIH HHS K08 NS051843-01A2 / NINDS NIH HHS R01 DK078184 / NIDDK NIH HHS R01 CA139043-01A1 / NCI NIH HHS R01 CA129387-03 / NCI NIH HHS U24 CA126608-04 / NCI NIH HHS R21 CA132096-01A1 / NCI NIH HHS R01 CA139043-03 / NCI NIH HHS K08 NS051843-04 / NINDS NIH HHS R01 DK078184-05 / NIDDK NIH HHS R01 DK078184-02 / NIDDK NIH HHS K08 NS051843-02 / NINDS NIH HHS R01 DK078184-01A1 / NIDDK NIH HHS R01 DK078184-03 / NIDDK NIH HHS R01 CA129387-02 / NCI NIH HHS U24 CA126608-03 / NCI NIH HHS R01 CA139043-02 / NCI NIH HHS U24 CA126608 / NCI NIH HHS R21 CA132096-02 / NCI NIH HHS
Language: English
Date published: 05/05/2011
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917664902771

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