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Molecular and Cellular Biology, August 2009, p. 4527-4538, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00200-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factor 2 Regulates Hepatic Lipid Metabolism{triangledown} ,{dagger}

Erinn B. Rankin,1,{ddagger} Jennifer Rha,1 Mary A. Selak,2 Travis L. Unger,1 Brian Keith,3 Qingdu Liu,1,4 and Volker H. Haase1,4*

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,1 Children's Hospital, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,2 Abramson Family Cancer Research Institute and Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania,3 Department of Medicine, Cancer Biology, Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee4

Received 12 February 2009/ Returned for modification 22 March 2009/ Accepted 8 June 2009

In mammals, the liver integrates nutrient uptake and delivery of carbohydrates and lipids to peripheral tissues to control overall energy balance. Hepatocytes maintain metabolic homeostasis by coordinating gene expression programs in response to dietary and systemic signals. Hepatic tissue oxygenation is an important systemic signal that contributes to normal hepatocyte function as well as disease. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2, respectively) are oxygen-sensitive heterodimeric transcription factors, which act as key mediators of cellular adaptation to low oxygen. Previously, we have shown that HIF-2 plays an important role in both physiologic and pathophysiologic processes in the liver. HIF-2 is essential for normal fetal EPO production and erythropoiesis, while constitutive HIF-2 activity in the adult results in polycythemia and vascular tumorigenesis. Here we report a novel role for HIF-2 in regulating hepatic lipid metabolism. We found that constitutive activation of HIF-2 in the adult results in the development of severe hepatic steatosis associated with impaired fatty acid β-oxidation, decreased lipogenic gene expression, and increased lipid storage capacity. These findings demonstrate that HIF-2 functions as an important regulator of hepatic lipid metabolism and identify HIF-2 as a potential target for the treatment of fatty liver disease.

* Corresponding author. Mailing address: Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, C-3119A, MCN, 1161 21st Avenue, Nashville, TN 37232. Phone: (615) 343-7254. Fax: (615) 322-6854. E-mail: volker.haase{at}vanderbilt.edu

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Division of Cancer and Radiation Biology, Department of Radiation Oncology, Stanford University, CCSR-South, Room 1255, 269 Campus Drive, Stanford, CA 94305.

Molecular and Cellular Biology, August 2009, p. 4527-4538, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00200-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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