Scavenger receptor BI promotes cytoplasmic accumulation of lipoproteins in clear-cell renal cell carcinoma (original) (raw)
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The Journal of Lipid Research, 2008
LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Administration of an adenovirus expressing LPL (AdLPL) into lrp 2 ldlr 2/2 vldlr 2/2 mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, inhibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their remnants positively correlated with LPL activity. This hepatic association was independent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp 2 ldlr 2/2 vldlr 2/2 mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI. The hepatic uptake of VLDL in lrp 2 ldlr 2/2 vldlr 2/2 mice is regulated by LPL activity and involves proteoglycans and SR-BI. J. Lipid Res. 2008. 49: 1553-1561. Supplementary key words lipoprotein lipase • low density lipoprotein receptor • very low density lipoprotein receptor • low density lipoprotein receptor-related protein • triglyceride-rich emulsion particles • transgenic mice • adenovirus-mediated gene transfer • apolipoprotein E
Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo
The Journal of Lipid Research, 2008
Scavenger receptor class B type I (SR-BI) functions as an HDL receptor that promotes the selective uptake of cholesteryl esters (CEs). The physiological role of SR-BI in VLDL metabolism, however, is largely unknown. SR-BI deficiency resulted in elevated VLDL cholesterol levels, both on chow diet and upon challenge with high-cholesterol diets. To specifically elucidate the role of SR-BI in VLDL metabolism, the plasma clearance and hepatic uptake of 125
Proceedings of the National Academy of Sciences, 1978
Selective delivery of cytotoxic anti-neoplastic drugs can diminish the severe side-effects associated with these drugs. Many malignant tumours express high levels of low-density lipoprotein (LDL) receptors on their membranes. Therefore, LDL may be used as a carrier to obtain selective delivery of anti-neoplastic drugs to tumours. The present study was performed to investigate the feasibility of the murine B16 tumour/mouse model for the evaluation of LDL-mediated tumour therapy. LDL binds with high affinity to LDL receptors on cultured B16 cells (Kd, 5.9+2.3 Yg ml -; Bmax, 206+23 ng LDL mg-1 cell protein). After binding and internalisation, LDL was very efficiently degraded: 724+ 19 ng LDL mgcell protein h-'. Chloroquine and ammonium chloride completely inhibited the degradation of LDL by the B16 cells, indicating involvement of lysosomes. LDL receptors were down-regulated by 70% after preincubation of B16 cells with 300 jg ml-l LDL, indicating that their expression is regulated by intracellular cholesterol. To evaluate the uptake of LDL by the B16 tumour in vivo, tissue distribution studies were performed in C57/Bl mice inoculated with B16 tumours. For these experiments, LDL was radiolabelled with tyramine cellobiose, a non-degradable label, which is retained in cells after uptake. At 24 h after injection of LDL, the liver, adrenals and the spleen were found to be the major organs involved in LDL uptake, with tissue-serum (T/S) ratios of 0.82+0.08, 1.17 + 0.20 and 0.69 + 0.08 respectively. Of all the other tissues, the tumour showed the highest uptake of LDL (T/S ratio of 0.40+0.07). A large part of the LDL uptake was receptor mediated, as the uptake of methylated LDL was much lower. Although the LDL uptake by the liver, spleen and adrenals is higher than that by the tumour, the LDL receptor-mediated uptake by these organs may be selectively down-regulated by methods that do not affect the expression of LDL receptors on tumour cells. It is concluded that the B16 tumour-bearing mouse constitutes a good model to evaluate the effectiveness of LDL-mediated delivery of cytotoxic (pro)drugs to tumours in vivo.
Arteriosclerosis, thrombosis, and vascular biology, 2017
Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- and antiatherogenic activities, respectively, within the vascular wall. However, the rate-limiting factors that mediate transendothelial transport of lipoproteins are yet little known. Therefore, we performed a high-throughput screen with kinase drug inhibitors to identify modulators of transendothelial LDL and HDL transport. Microscopy-based high-content screening was performed by incubating human aortic endothelial cells with 141 kinase-inhibiting drugs and fluorescent-labeled LDL or HDL. Inhibitors of vascular endothelial growth factor (VEGF) receptors (VEGFR) significantly decreased the uptake of HDL but not LDL. Silencing of VEGF receptor 2 significantly decreased cellular binding, association, and transendothelial transport of (125)I-HDL but not (125)I-LDL. RNA interference with VEGF receptor 1 or VEGF receptor 3 had no effect. Binding, uptake, and transport of HDL but not LDL were s...
Tumor Biology, 2012
Tumour are characterised by a high content of cholesteryl esters (CEs) stored in lipid droplets purported to be due to a high rate of intracellular esterification of cholesterol. To verify whether and which pathways involved in CE accumulation are essential in tumour proliferation, the effect of CE deprivation, from both exogenous and endogenous sources, on CEM-CCRF cells was investigated. Cholesterol synthesis, esterification and content, low-density lipoprotein (LDL) binding and highdensity lipoprotein (HDL)-CE uptake were evaluated in cultured in both conventional and delipidated bovine serum with or without oleic or linoleic acids, cholesteryl oleate, LDL and HDL. High content of CEs in lipid droplets in this cell line was due to esterification of both newly synthesised cholesterol and that obtained from hydrolysis of LDL; moreover, a significant amount of CE was derived from HDL-CE uptake. Cell proliferation was slightly affected by either acute or chronic treatment up to 400 μM with Sz-58035, an acyl-cholesteryl cholesterol esterification inhibitor (ACAT); although when the enzyme activity was continuously inhibited, CE content in lipid droplets was significantly higher than those in control cells. In these cells, analysis of intracellular and medium CEs revealed a profile reflecting the characteristics of bovine serum, suggesting a plasma origin of CE molecules. Cell proliferation arrest in delipidated medium was almost completely prevented in the first 72 h by LDL or HDL, although in subsequent cultures with LDL, it manifested an increasing mortality rate. This study suggests that high content of CEs in CEM-CCRF is mainly derived from plasma lipoproteins and that part of CEs stored in lipid droplets are obtained after being taken up from HDL. This route appears to be up-regulated according to cell requirements and involved in low levels of c-HDL during cancer. Moreover, the dependence of tumour cells on a source of lipoprotein provides a novel impetus in developing therapeutic strategies for use in the treatment of some tumours.
U937 is a monocytic cell-line originally derived from a histiocytic lymphoma. In serum-free medium the growth of U937 cells was stimulated by addition of low density lipoprotein (LDL). Methylation of LDL impaired its ability to be taken up in U937 cells as well as the capacity to stimulate the growth of these cells. Pretreatment of U937 cells with a monoclonal antibody against the LDL receptor was also found to completely block the growth-promoting effect of LDL. Exposure of U937 cells to liposomes with a lipid composition similar to that of LDL did not stimulate the growth rate. These findings demonstrate that growth of U937 cells under serum-free conditions is related to the amount of LDL ingested by the cells and that this uptake is mediated by binding of LDL to the LDL receptor. To determine if LDL-induced growth of U937 cells can be used to identify LDL with decreased binding to the LDL receptor, U937 cells were incubated with LDL isolated from a patient with familial defective apolipoprotein B-100 and from subjects with various lipoprotein phenotypes. LDL containing defective apolipoprotein B-100 was found to be less than half as effective as LDL from normolipidemic controls in stimulating growth of U937 cells. LDL isolated from patients with hyperlipoproteinemia type IIa and IV did not differ from normal LDL in their ability to promote growth of U937 cells. B The present results suggest that LDL-induced growth of U937 cells may be used as an assay to identify defective receptor binding of LDL. -Fmstegird, J., A. Hamsten, M. Gidlund, and J. Nilsson. Low density lipoprotein-induced growth of U937 cells: a novel method to determine the receptor binding of low density lipoprotein. J Lipid Res. 1990. 31: 37-44. Supplementary key words sis familial hypercholesterolemia cholesterol cell growth atherosclero-Abbreviations: VLDL, very low density lipoprotein: HDL, high density lipoprotein; LDL, low density lipoprotein; FH, familial hypercholesterolemia; RFLP, restriction fragment length polymorphism.