Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation

Ackerman, D., Tumanov, S., Qiu, B., Michalopoulou, E., Spata, M., Azzam, A., Xie, H., Simon, M. C. and Kamphorst, J. J. (2018) Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation. Cell Reports, 24(10), 2596-2605.e5. (doi:10.1016/j.celrep.2018.08.015) (PMID:30184495) (PMCID:PMC6137821)

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Abstract

Lipid droplets, which store triglycerides and cholesterol esters, are a prominent feature of clear cell renal cell carcinoma (ccRCC). Although their presence in ccRCC is critical for sustained tumorigenesis, their contribution to lipid homeostasis and tumor cell viability is incompletely understood. Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions. Functionally, hypoxia leads to increased fatty acid saturation through inhibition of the oxygen-dependent stearoyl-CoA desaturase (SCD) enzyme. Triglycerides counter a toxic buildup of saturated lipids, primarily by releasing the unsaturated fatty acid oleate (the principal product of SCD activity) from lipid droplets into phospholipid pools. Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-κB transcription factor. Our work demonstrates that triglycerides promote homeostasis by “buffering” specific fatty acids.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michalopoulou, Evdokia and Kamphorst, Dr Jurre and Tumanov, Dr Sergey
Authors: Ackerman, D., Tumanov, S., Qiu, B., Michalopoulou, E., Spata, M., Azzam, A., Xie, H., Simon, M. C., and Kamphorst, J. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Reports 24(10): 2596-2605.e5
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
655161The effect of tumour microenvironment on the metabolism of pancreatic cancer cellsJurre KamphorstCancer Research UK (CRUK)17728ICS - BEATSON INSTITUTE FOR CANCER RES.