PMID- 29176561 OWN - NLM STAT- MEDLINE DCOM- 20181217 LR - 20240213 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 8 IP - 1 DP - 2017 Nov 24 TI - HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. PG - 1769 LID - 10.1038/s41467-017-01965-8 [doi] LID - 1769 AB - 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. FAU - Du, Weinan AU - Du W AD - Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Zhang, Luchang AU - Zhang L AD - Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Brett-Morris, Adina AU - Brett-Morris A AD - Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Aguila, Brittany AU - Aguila B AD - Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Kerner, Janos AU - Kerner J AD - Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Hoppel, Charles L AU - Hoppel CL AD - Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. AD - Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Puchowicz, Michelle AU - Puchowicz M AD - Department of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Serra, Dolors AU - Serra D AD - Department of Biochemistry and Physiology, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y la Nutricion (CIBEROBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain. FAU - Herrero, Laura AU - Herrero L AUID- ORCID: 0000-0003-4244-4673 AD - Department of Biochemistry and Physiology, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y la Nutricion (CIBEROBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain. FAU - Rini, Brian I AU - Rini BI AD - Department of Hematology and Oncology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Campbell, Steven AU - Campbell S AD - Department of Urology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44106, USA. FAU - Welford, Scott M AU - Welford SM AD - Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. scott.welford@case.edu. LA - eng GR - P30 CA043703/CA/NCI NIH HHS/United States GR - R21 CA178157/CA/NCI NIH HHS/United States GR - UL1 TR000439/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171124 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Basic Helix-Loop-Helix Transcription Factors) RN - 0 (Fatty Acids) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 1B37H0967P (endothelial PAS domain-containing protein 1) RN - EC 2.3.1.21 (CPT1A protein, human) RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) SB - IM MH - Animals MH - Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism MH - Carcinogenesis MH - Carcinoma, Renal Cell/genetics/*metabolism MH - Carnitine O-Palmitoyltransferase/genetics/metabolism MH - Cell Line, Tumor MH - Fatty Acids/*metabolism MH - Female MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism MH - Kidney Neoplasms/genetics/*metabolism MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mitochondria/metabolism PMC - PMC5701259 COIS- The authors declare no competing financial interests. EDAT- 2017/11/28 06:00 MHDA- 2018/12/18 06:00 PMCR- 2017/11/24 CRDT- 2017/11/28 06:00 PHST- 2016/10/12 00:00 [received] PHST- 2017/10/30 00:00 [accepted] PHST- 2017/11/28 06:00 [entrez] PHST- 2017/11/28 06:00 [pubmed] PHST- 2018/12/18 06:00 [medline] PHST- 2017/11/24 00:00 [pmc-release] AID - 10.1038/s41467-017-01965-8 [pii] AID - 1965 [pii] AID - 10.1038/s41467-017-01965-8 [doi] PST - epublish SO - Nat Commun. 2017 Nov 24;8(1):1769. doi: 10.1038/s41467-017-01965-8.