Cell Reports
Volume 24, Issue 10, 4 September 2018, Pages 2596-2605.e5
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Report
Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation

https://doi.org/10.1016/j.celrep.2018.08.015Get rights and content
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Highlights

  • Hypoxia influences the FA composition of TGs more than other lipid classes

  • TGs maintain the cell’s FA saturation index by active oleate exchange

  • Release of TG-resident oleate during hypoxia prevents production of toxic lipids

  • Disrupting TG synthesis compromises tumor growth

Summary

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.

Keywords

cancer metabolism
clear cell renal cell carcinoma
diglyceride acyltransferase
fatty acid saturation
hypoxia
lipid droplets
lipid homeostasis
lipidomics
stable isotope tracing
triglycerides

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These authors contributed equally

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