Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective uptake of high-density lipoprotein (HDL)-associated cholesteryl esters (CE), i.e. lipid uptake independent of HDL particle uptake, delivers CE to the liver and steroidogenic tissues in vivo and in vitro. From human plasma HDL, two major subpopulations of particles can be isolated: one contains both apolipoprotein (apo) A-I and apo A-II (designated LpA-I:A-II) as dominant protein components, whereas in the other apo A-II is absent (LpA-I). In this study, selective CE uptake from LpA-I and LpA-I:A-II by cultured cells was investigated. LpA-I and LpA-I:A-II were isolated by immunoaffinity chromatography from human plasma high-density lipoprotein3 (HDL3, d = 1.125-1.21 g/ml) and both particles were radiolabeled in the protein (125I) as well as in the CE moiety ([3H]cholesteryl oleyl ether ([3H]CEt)). Several control experiments validated the labeling methodology applied. To investigate selective CE uptake, human Hep G2 hepatoma cells, human hepatocytes in primary culture and human skin fibroblasts were incubated in medium containing doubly radiolabeled LpA-I or LpA-I:A-II particles. Thereafter cellular tracer content was determined. For each cell type the rate of apparent lipoprotein particle uptake according to the lipid tracer ([3H]CEt) was in substantial excess over that due to the protein tracer (125I), demonstrating selective CE uptake from LpA-I as well as from LpA-I:A-II. This difference in uptake between [3H]CEt and 125I, i.e. the rate of apparent selective CE uptake, was significantly higher for LpA-I compared to LpA-I:A-II, and this was dose- as well as time-dependent. Thus in human hepatic cell and fibroblasts, CE are selectively taken up to a higher extent from LpA-I compared to LpA-I:A-II. These results may suggest that LpA-I particles of the human plasma HDL fraction may be those lipoproteins which more efficiently deliver CE to the liver via the selective uptake pathway whereas LpA-I:A-II may play a less important role.
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PMID:Selective uptake of cholesteryl esters from high-density lipoprotein-derived LpA-I and LpA-I:A-II particles by hepatic cells in culture. 974 29

Selective uptake of high-density lipoprotein- (HDL-) associated cholesteryl esters (CE), i.e. lipid uptake independent from particle uptake, delivers CE to the liver and steroidogenic tissues in vivo. In vitro, besides hepatocytes and steroidogenic cells many other cell types selectively take up HDL CE. Hepatic lipase (HL) stimulates the internalisation of apoprotein (apo) B-containing lipoproteins by hepatocytes independent from lipolysis. In this study the role of HL in the hepatic metabolism of apo A-I-containing lipoproteins, i.e. HDL, was investigated. HDL3 (d = 1.125-1.21 g/ml) was radiolabeled in its protein (125I) and in its CE moiety ([3H]cholesteryl oleyl ether, ([3H]CEt)). HL originated from tissue culture media of hepatoma cells and from post-heparin plasma. Human Hep 3B hepatoma cells incubated in medium containing radiolabeled HDL3. In the absence of HL, the rate of apparent HDL3 particle uptake according to the lipid tracer ([3H]CEt) was in most cases in approximately 10-fold excess on that due to the protein label (125I), indicating selective CE uptake from HDL3. Addition of HL to these incubations increased the cellular uptake of [3H]CEt and of 125I from HDL3 and quantitatively the most prominent effect was an up to approximately 2.5-fold stimulation of apparent selective CE uptake ([3H]CEt-125I). This increase in selective CE uptake was observed in the presence of tetrahydrolipstatin, an inhibitor of the catalytically active site of HL, suggesting that this HL effect is independent from lipolysis. HL binds to cell surface heparan sulfate proteoglycans. To explore the role of these molecules for the HL effect on selective CE uptake, hepatoma cells were depleted of proteoglycans or Chinese hamster ovary (CHO) cells deficient in proteoglycan synthesis were used. Proteoglycan-deficiency reduced the HL-mediated increase in selective uptake by more than 80%. To investigate if low-density lipoprotein (LDL) receptors or the LDL receptor-related protein (LRP) are involved in the HL effect on selective CE uptake, murine embryonic fibroblasts (MEF) were used which are deficient in these receptors; alternatively, monensin, an inhibitor of endocytosis was present in the medium of Hep 3B cells during the uptake assay for labeled HDL3. These experiments yielded no evidence for a role of LDL receptors or LRP in the HL-mediated increase in selective CE uptake. In summary, HL mediates an increase in HDL3 selective CE uptake by human Hep 3B hepatoma cells. This HL effect is independent from lipolysis and independent from LRP and LDL receptors. However this HL effect is susceptible to cell surface proteoglycan deficiency. The potential physiologic implication is that HL modifies HDL selective CE uptake by the liver in vivo and such an effect could play a role in reverse cholesterol transport.
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PMID:Hepatic lipase mediates an increase in selective uptake of high-density lipoprotein-associated cholesteryl esters by human Hep 3B hepatoma cells in culture. 986 76

Class B scavenger receptors (SR-Bs) interact with native, acetylated and oxidized low-density lipoprotein (LDL, AcLDL and OxLDL), high-density lipoprotein (HDL3) and maleylated BSA (M-BSA). The aim of this study was to analyze the catabolism of CD36- and LIMPII-analogous-1 (CLA-1), the human orthologue for the scavenger receptor class B type I (SR-BI), and CD36 ligands in HepG2 (human hepatoma) cells. Saturation binding experiments revealed moderate-affinity binding sites for all the SR-B ligands tested with dissociation constants ranging from 20 to 30 microg.mL-1. Competition binding studies at 4 degrees C showed that HDL and modified and native LDL share common binding site(s), as OxLDL competed for the binding of 125I-LDL and 125I-HDL3 and vice versa, and that only M-BSA and LDL may have distinct binding sites. Degradation/association ratios for SR-B ligands show that LDL is very efficiently degraded, while M-BSA and HDL3 are poorly degraded. The modified LDL degradation/association ratio is equivalent to 60% of the LDL degradation ratio, but is three times higher than that of HDL3. All lipoproteins were good cholesteryl ester (CE) donors to HepG2 cells, as a 3.6-4.7-fold CE-selective uptake ([3H]CE association/125I-protein association) was measured. M-BSA efficiently competed for the CE-selective uptake of LDL-, OxLDL-, AcLDL- and HDL3-CE. All other lipoproteins tested were also good competitors with some minor variations. Hydrolysis of [3H]CE-lipoproteins in the presence of chloroquine demonstrated that modified and native LDL-CE were mainly hydrolyzed in lysosomes, whereas HDL3-CE was hydrolyzed in both lysosomal and extralysosomal compartments. Inhibition of the selective uptake of CE from HDL and native modified LDL by SR-B ligands clearly suggests that CLA-1 and/or CD36 are involved at least partially in this process in HepG2 cells.
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PMID:Uptake and fate of class B scavenger receptor ligands in HepG2 cells. 1010 54

We have previously shown that hepatic lipase (HL) is inactive when bound to purified heparan sulfate proteoglycans and can be liberated by HDL and apolipoprotein A-I (apoA-I), but not by LDL or VLDL. In this study, we show that HDL is also able to displace HL directly from the surface of the hepatoma cell line, HepG2, and Chinese hamster ovary cells stably overexpressing human HL. ApoA-I is more efficient at displacing cell surface HL than is HDL, and different HDL classes vary in their ability to displace HL from the cell surface. HDL2s have a greater capacity to remove HL from the cell surface and intracellular compartments, as compared with the smaller HDL particles. The different HDL subclasses also uniquely affect the activity of the enzyme. HDL2 stimulates HL-mediated hydrolysis of VLDL-triacylglycerol, while HDL3 is inhibitory. Inhibition of VLDL hydrolysis appears to result from a decreased interlipoprotein shuttling of HL between VLDL and the smaller, more dense HDL particles. This study suggests that high HDL2 levels are positively related to efficient triacylglycerol hydrolysis by their ability to enhance the liberation of HL into the plasma compartment and by a direct stimulation of VLDL-triacylglycerol hydrolysis.
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PMID:HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol. 1256 72

Serum amyloid A (SAA) circulates bound to HDL3 during the acute-phase response (APR), and recent evidence suggests that elevated levels of SAA may be a risk factor for cardiovascular disease. In this study, SAA-HDL was produced in vivo during the APR and without the APR by injection of an adenoviral vector expressing human SAA-1. SAA-HDL was also produced in vitro by incubating mouse HDL with recombinant mouse SAA and by SAA-expressing cultured hepatoma cells. Whether produced in vivo or in vitro, SAA-HDL floated at a density corresponding to that of human HDL3 (d 1.12 g/ml) separate from other apolipoproteins, including apolipoprotein A-I (apoA-I; d 1.10 g/ml) when either apoA-I or apolipoprotein E (apoE) was present. In the absence of both apoA-I and apoE, SAA was found in VLDL and LDL, with low levels in the HDL and the lipid-poor fractions suggesting that other HDL apolipoproteins are incapable of facilitating the formation of SAA-HDL. We conclude that SAA does not exist in plasma as a lipid-free protein. In the presence of HDL-associated apoA-I or apoE, SAA circulates as SAA-HDL with a density corresponding to that of human HDL3. In the absence of both apoA-I and apoE, SAA-HDL is not formed and SAA associates with any available lipoprotein.
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PMID:Influence of apoA-I and apoE on the formation of serum amyloid A-containing lipoproteins in vivo and in vitro. 1459 2

The scavenger receptor class B, type I (SR-BI) mediates cholesteryl esters (CE) selective uptake from low density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. In a number of tissues expressing caveolin, SR-BI is localized in caveolae. We show using detergent-free sucrose gradients that SR-BI is found in membrane rafts devoid of caveolin-1 in the human hepatoma HepG2 cell. Perturbation of the structure of HepG2 cell membrane rafts with cholesterol oxidase or sphingomyelinase decreased LDL-CE association due to selective uptake by 60%, while HDL3-CE selective uptake was increased 2.3-fold by cholesterol oxidase but was not affected by sphingomyelinase. Sequestration of membrane cholesterol with filipin III decreased LDL-CE selective uptake by 25%, while it had no effect on HDL3-CE selective uptake. Extraction of cell membrane cholesterol with beta-cyclodextrin increased LDL- and HDL3-CE selective uptake by 1.6-fold and 3-fold, respectively. We found that CE-selective uptake from both HDL and LDL occurs by a pathway involving retro-endocytosis in HepG2 cells. An analysis of the effect of SR-BI level on the expression of critical lipid sensor and lipid binding proteins was conducted with stable transformants of HepG2 cell overexpressing SR-BI. We found that liver-type fatty acid binding protein expression level is higher in SR-BI-overexpressing cells and that caveolin-1 and sterol response element binding protein-2 levels are reduced. Thus, in this hepatic cell model, SR-BI is associated with membrane rafts devoid of caveolin and its expression affects intracellular lipid binding and lipid sensor proteins. SR-BI-dependent LDL- and HDL-CE selective uptake are affected differently by the integrity of membrane rafts, but both occur by a retroendocytic pathway in HepG2 cells.
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PMID:Localization and regulation of SR-BI in membrane rafts of HepG2 cells. 1522 91


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