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

Author

Listed:
  • 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
    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
    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III)

  • Laura Herrero

    (Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona
    Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III)

  • 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)

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.

Suggested Citation

  • 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 & Scott M. Wel, 2017. "HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01965-8
    DOI: 10.1038/s41467-017-01965-8
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    Cited by:

    1. Xuewu Sui & Kun Wang & Kangkang Song & Chen Xu & Jiunn Song & Chia-Wei Lee & Maofu Liao & Robert V. Farese & Tobias C. Walther, 2023. "Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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