HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism

Weinan Du, Luchang Zhang, Adina Brett-Morris, Brittany Aguila, Janos Kerner, Charles L. Hoppel, Michelle Puchowicz, Dolors Serra, Laura Herrero, Brian I. Rini, Steven Campbell and Scott M. Welford ()
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Weinan Du: Case Western Reserve University School of Medicine
Luchang Zhang: Case Western Reserve University School of Medicine
Adina Brett-Morris: Case Western Reserve University School of Medicine
Brittany Aguila: Case Western Reserve University School of Medicine
Janos Kerner: Case Western Reserve University School of Medicine
Charles L. Hoppel: Case Western Reserve University School of Medicine
Michelle Puchowicz: Case Western Reserve University School of Medicine
Dolors Serra: Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona
Laura Herrero: Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona
Brian I. Rini: Department of Hematology and Oncology, Cleveland Clinic Foundation
Steven Campbell: Department of Urology, Cleveland Clinic Foundation
Scott M. Welford: Case Western Reserve University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. Alterations in the VHL tumor suppressor stabilizing the hypoxia-inducible factors (HIFs) are the most prevalent molecular features of clear cell tumors. The significance of lipid deposition remains undefined. We describe the mechanism of lipid deposition in ccRCC by identifying the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A (CPT1A), as a direct HIF target gene. CPT1A is repressed by HIF1 and HIF2, reducing fatty acid transport into the mitochondria, and forcing fatty acids to lipid droplets for storage. Droplet formation occurs independent of lipid source, but only when CPT1A is repressed. Functionally, repression of CPT1A is critical for tumor formation, as elevated CPT1A expression limits tumor growth. In human tumors, CPT1A expression and activity are decreased versus normal kidney; and poor patient outcome associates with lower expression of CPT1A in tumors in TCGA. Together, our studies identify HIF control of fatty acid metabolism as essential for ccRCC tumorigenesis.

Date: 2017
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DOI: 10.1038/s41467-017-01965-8

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