Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Huang, J.
Role of lipoprotein homeostasis in tumor growth
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] ; 2015. pp.
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- Autor*innen der Med Uni Graz:
- Huang Jianfeng
- Betreuer*innen:
- Höfler Gerald
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- Abstract:
- [Background] Obesity is considered as one of the most common public health problems worldwide. Recent evidence strongly linked obesity to an increased risk for developing a broad range of malignant tumors including lymphoma. Notably, tumor development and especially cancer-associated cachexia could influence the host lipid metabolism. The bidirectional causality between tumor development and host lipid abnormality is, remarkably, largely unexplored. [Methods] We used Bcr/Abl transformed B cells (TPBC) to determine the impact and the underlying mechanisms of aggressive lymphoma formation on systemic lipid mobilization and turnover. Two lipid lowering strategies, a lipid lowering drug, fenofibrate, and two VLDL production-deficient mouse models – carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH)- and phosphatidylethanolamine N-methyltransferase (PEMT)- knockout mice, were used to determine whether limitation of exogenous lipid supply could influence tumor growth. [Results] In mice, B-cell tumor size significantly correlated with depletion of white adipose tissues (WAT). Tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Metabolic labeling assays in primary hepatocytes isolated from tumor-bearing (Tu) mice showed accelerated synthesis of free cholesterol from [3H]-acetate and increased esterification of [3H]-oleate into cholesteryl ester (CE) and triglyceride (TG) tumor, resulting in increased secretion of TG/CE into the growth media. In line, the hepatic VLDL production rate was increased in tumor-bearing mice compared to non-tumor bearing controls (Non-Tu). Together with perturbed clearance of TG-rich lipoproteins from the bloodstream as determined by a fat tolerant test and by TG hydrolase activities assays, enhanced VLDL production leads to hypertriglyceridemia in Tu mice. Moreover, decreased protein levels of hepatic LDLR and elevated concentrations of plasma PCSK9 were observed in the Tu group, leading to hypercholesterolemia. The tumor-supportive function of very low- /low- density lipoproteins (VLDL/LDL) on cell growth was confirmed in vitro. Lipoprotein-deficient serum (LPDS) media drastically reduced tumor B-cell proliferation and provoked apoptosis. Supplementation of VLDL/LDL or cholesterol, and, to a lesser extent, high density lipoproteins (HDL) could reverse effects conferred by LPDS. Further support this hypothesis stems from the results of lipid lowering strategies. Both the lipid-lowering drug fenofibrate and Ces3/TGH deficiency in mice significantly reversed tumor-induced hyperlipidemia and suppressed tumor growth. Fenofibrate stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. The mechanism of protection against tumor growth in Ces3/Tgh-/- mice could be attributed to the reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decreased LDL turnover. Interestingly, Pemt-/- mice failed to exert such an effect and, thus, tumor growth was not suppressed. [Conclusion] Our data demonstrate that TPBC tumor-induced hyperlipidemia encompasses a feedback loop to support tumor growth in part by providing pro-tumorigenic LDL-cholesterol. Fenofibrate-associated effects on hepatic lipid metabolism and deprivation of serum lipids, as well as protection of hepatic LDLR from PCSK9-mediated degradation in Ces3/Tgh-/- mice, are both capable to suppress B-cell lymphoma growth. These findings may lead to novel treatment strategies against tumor growth.