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

Oncogene volume 30, pages 2147–2160 (2011)Cite this article

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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;VhlF/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 pO2. 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.

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Acknowledgements

We thank Drs Frank J Gonzalez, Volker H Haase, William Y Kim and William G Kaelin Jr for mouse strains and reagents, Dr Michael Brown for discussions, and Dr Jay D Horton for critically reading the manuscript, TianTeng He for help with liver perfusion experiments, and members of the Brugarolas lab for discussions. This work was supported by the following grants to J.B: K08NS051843, American Cancer Society Research Scholar Grant (115739) and RO1CA129387 as well as an RO1DK078184 to S.B. MRI was performed in conjunction with R01CA139043 (R.P.M.) R21CA132096 (V.D.K.) and the UT Southwestern small animal imaging research program U24 CA126608 and P41 RR02584. S.P.-L. was supported in part by a fellowship from the Generalitat Valenciana (Spain). J.B. is a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern.

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Authors and Affiliations

  1. Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    B Kucejova, S Peña-Llopis & J Brugarolas

  2. Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA

    B Kucejova, S Peña-Llopis & J Brugarolas

  3. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    B Kucejova, S Peña-Llopis, X-J Xie & J Brugarolas

  4. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    N E Sunny, X Fu & S C Burgess

  5. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    A D Nguyen & R DeBose-Boyd

  6. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    R Hallac, R P Mason & V D Kodibagkar

  7. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    R J DeBerardinis

  8. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    X-J Xie

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Kucejova, B., Sunny, N., Nguyen, A. et al. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. Oncogene 30, 2147–2160 (2011). https://doi.org/10.1038/onc.2010.587

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