scholarly journals Endocytosis of very low-density lipoprotein particles: an unexpected mechanism for lipid acquisition by breast cancer cells

2019 ◽  
Author(s):  
Leslie E. Lupien ◽  
Katarzyna Bloch ◽  
Jonas Dehairs ◽  
William W. Feng ◽  
Wilson L. Davis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
De Novo ◽  
Culture Media ◽  
Low Density Lipoprotein ◽  
Tumor Biology ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density

ABSTRACTWe previously described the expression of CD36 and lipoprotein lipase (LPL) by breast cancer (BC) cells and tissues, and the growth-promoting effect of very low-density lipoprotein (VLDL) supplementation observed in BC cell lines only in the presence of LPL. We now describe the deployment of LPL by BC cells. Our data support a model in which LPL is bound to a heparin-like heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to rapidly internalize intact lipoproteins via receptor-mediated endocytosis. We further observe substantial alterations in gene expression programs related to pathways for lipid acquisition (synthesis vs. uptake) in response to each the availability of exogenous triglyceride in tissue culture media and LPL expression status. Current literature emphasizesde novofatty acid synthesis as the paramount mechanism for lipid acquisition by cancer cells. Our findings indicate that exogenous lipid uptake can serve as an important method of lipid acquisition for cancer cells, alongsidede novolipogenesis, and that the relative reliance on these two modes of lipid acquisition may vary among different BC cell lines and in response to nutrient availability. This concept has obvious implications for the development of therapies aimed at the lipid dependence of many different cancer types. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.

scholarly journals Study of Acetyl Low Density Lipoprotein and β-Very Low Density Lipoprotein Metabolism in Macrophage Cell Lines

1988 ◽  
Vol 15 (8) ◽  
pp. 1647-1651
Author(s):  
Hideki HIDAKA ◽  
Yuzuru NAKAZIMA ◽  
Mariko HARADA ◽  
Takamitsu NAKANO ◽  
Takahiko AOKI ◽  
...  
Keyword(s):  
Cell Lines ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Macrophage Cell

scholarly journals Effects of oleic acid on the biosynthesis of lipoprotein apoproteins and distribution into the very-low-density lipoprotein by the isolated perfused rat liver

1988 ◽  
Vol 251 (3) ◽  
pp. 809-816 ◽  
Author(s):  
W H Salam ◽  
H G Wilcox ◽  
M Heimberg
Keyword(s):  
Oleic Acid ◽  
Rat Liver ◽  
De Novo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Isolated Perfused Rat Liver ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Perfused Rat Liver ◽  
Fasted Rats

The effects of oleic acid on the biosynthesis and secretion of VLDL (very-low-density-lipoprotein) apoproteins and lipids were investigated in isolated perfused rat liver. Protein synthesis was measured by the incorporation of L-[4,5-3H]leucine into the VLDL apoproteins (d less than 1.006) and into apolipoproteins of the whole perfusate (d less than 1.21). Oleate did not affect incorporation of [3H]leucine into total-perfusate or hepatic protein. The infusion of oleate, however, increased the mass and radioactivity of the VLDL apoprotein in proportion to the concentration of oleate infused. Uptake of oleate was similar with livers from fed or fasted animals. Fasting itself (24 h) decreased the net secretion and incorporation of [3H]leucine into total VLDL apoprotein and decreased the output of VLDL protein by the liver. A linear relationship existed between the output of VLDL triacylglycerol (mumol/h per g of liver) and secretion and/or synthesis of VLDL protein. Net output of VLDL cholesterol and phospholipid also increased linearly with VLDL-triacylglycerol output. Oleate stimulated incorporation of [3H]leucine into VLDL apo (apolipoprotein) E and apo C by livers from fed animals, and into VLDL apo Bh, B1, E and C by livers from fasted rats. The incorporation of [3H]leucine into individual apolipoproteins of the total perfusate lipoprotein (d less than 1.210 ultracentrifugal fraction) was not changed significantly by oleate during perfusion of livers from fed rats, suggesting that the synthesis de novo of each apolipoprotein was not stimulated by oleate. This is in contrast with that observed with livers from fasted rats, in which the synthesis of the total-perfusate lipoprotein (d less than 1.210 fraction) apo B, E and C was apparently stimulated by oleate. The observations with livers from fed rats suggest redistribution of radioactive apolipoproteins to the VLDL during or after the process of secretion, rather than an increase of apoprotein synthesis de novo. It appears, however, that the biosynthesis of apo B1, Bh, E and C was stimulated by oleic acid in livers from fasted rats. Since the incorporations of [3H]leucine into the VLDL and total-perfusate apolipoproteins were increased in fasted-rat liver when the fatty acid was infused, part of the apparent stimulated synthesis of the VLDL apoprotein may be in response to the increased formation and secretion of VLDL lipid.

scholarly journals A Role for ER-Beta in the Effects of Low-Density Lipoprotein Cholesterol and 27-Hydroxycholesterol on Breast Cancer Progression: Involvement of the IGF Signalling Pathway?

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 94
Author(s):  
Reham M. Mashat ◽  
Hanna A. Zielinska ◽  
Jeff M. P. Holly ◽  
Claire M. Perks
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Oestrogen Receptor ◽  
Breast Cancer Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Migration And Invasion ◽  
Low Density ◽  
Igf I ◽  
Positive Breast Cancer

Cholesterol—in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)—is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.

scholarly journals A Dual Sugar Challenge Test for Lipogenic Sensitivity to Dietary Fructose

2011 ◽  
Vol 96 (3) ◽  
pp. 861-868 ◽  
Author(s):  
Lisa C. Hudgins ◽  
Thomas S. Parker ◽  
Daniel M. Levine ◽  
Marc K. Hellerstein
Keyword(s):  
De Novo ◽  
Low Density Lipoprotein ◽  
Challenge Test ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Dose Effect ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Repeated Doses ◽  
Dietary Sugar

Context: Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in dyslipidemia, fatty liver, and insulin resistance. Objective: The aim of the study was to develop a simple outpatient tolerance test for lipogenic sensitivity to dietary sugar. Design and Setting: In inpatients given repeated doses of fructose, protocol 1 compared the acute increase in DNL determined from the percentage of palmitate (“new palmitate”) and the percentage of isotopically labeled palmitate (“%DNL”) in very low-density lipoprotein triglyceride (TG). Protocol 2 compared the increase in new palmitate in outpatients given three different sugar beverages in a randomized crossover design. Participants: There were 15 lean and overweight volunteers in protocol 1 and 15 overweight volunteers in protocol 2. Interventions: In protocol 1, subjects received 1.4 g/kg fructose in divided oral doses over 6 h; in protocol 2, subjects received 0.5 g/kg fructose, 0.5 g/kg fructose plus 0.5g/kg glucose, or 1 g/kg fructose plus 1g/kg glucose each as a single oral bolus. Main Outcome Measures: We measured the increase in DNL by two methods. Results: After repeated doses of fructose, new palmitate was significantly correlated with the increase in %DNL (Δ, r = 0.814; P < 0.001) and with fasting insulin levels (area under the curve, r = 0.754; P = 0.001). After a single sugar dose, new palmitate showed a dose effect and was greater after fructose plus glucose. Very low-density lipoprotein TG and total TG significantly increased in both protocols. Conclusions: A single oral bolus of fructose and glucose rapidly increases serum TG and TG palmitate in overweight subjects. A dual sugar challenge test could prove useful to identify individuals at risk for carbohydrate-induced dyslipidemia and other adverse effects of increased DNL.

scholarly journals Impaired-Inactivation of FoxO1 Contributes to Glucose-Mediated Increases in Serum Very Low-Density Lipoprotein

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3566-3576 ◽  
Author(s):  
Ke Wu ◽  
David Cappel ◽  
Melissa Martinez ◽  
John M. Stafford
Keyword(s):  
Blood Glucose ◽  
De Novo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Experimental Conditions ◽  
Adenoviral Delivery

For patients with diabetes, insulin resistance and hyperglycemia both contribute to increased serum triglyceride in the form of very low-density lipoprotein (VLDL). Our objective was to define the insulin conditions in which hyperglycemia promotes increased serum VLDL in vivo. We performed hyperglycemic-hyperinsulinemic clamp studies and hyperglycemic-hypoinsulinemic clamp studies in rats, with metabolic tracers for glucose flux and de novo fatty acid synthesis. When blood glucose was clamped at hyperglycemia (17 mm) for 2 h under hyperinsulinemic conditions (4 mU/kg · min), serum VLDL levels were not increased compared with baseline. We speculated that hyperinsulinemia minimized glucose-mediated VLDL changes and performed hyperglycemic-hypoinsulinemic clamp studies in which insulin was clamped near fasting levels with somatostatin (17 mm blood glucose, 0.25 mU/kg · min insulin). Under low-insulin conditions, serum VLDL levels were increased 4.7-fold after hyperglycemia, and forkhead box O1 (FoxO1) was not excluded from the nucleus of liver cells. We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL. We found that, when the ability of insulin to inactivate FoxO1 is blocked after adenoviral delivery of constitutively active FoxO1, glucose increased serum VLDL triglyceride when given both by ip glucose tolerance testing (3.5-fold increase) and by a hyperglycemic clamp (4.6-fold). Under both experimental conditions in which insulin signaling to FoxO1 was impaired, we found increased activation of carbohydrate response element binding protein. These data suggest that glucose more potently promotes increased serum VLDL when insulin action is impaired, with either low insulin levels or disrupted downstream signaling to the transcription factor FoxO1.

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