Journal
CELL REPORTS
Volume 15, Issue 2, Pages 336-348Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.03.020
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Funding
- Women and Children Health Research Institute
- Canadian Institutes of Health Research [MOP-69043]
- Austria Science Fund (FWF) [W1226 DK, SFB LIPOTOX F30]
- European Research Council Advanced Grant LIPOCHEX
- Austrian Science Fund (FWF) [P27070] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [F 3004] Funding Source: researchfish
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The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH) knockout mice. In Ces3/Tgh(-/-) tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh(-/-) mice. Mechanistically, reduced tumor growth in Ces3/Tgh(-/-) mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth.
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