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

The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) is a cell-surface glycoprotein of 4525 amino acids that functions as a hepatic endocytosis receptor for several plasma proteins. These include alpha 2-macroglobulin-protease complexes, free plasminogen activators as well as plasminogen activators complexed with their inhibitors, and beta-migrating very low density lipoproteins complexed with either apolipoprotein E or lipoprotein lipase. In the current study we used human and rat hepatoma cell lines to demonstrate that LRP can mediate the degradation of tissue factor pathway inhibitor (TFPI), a Kunitz-type plasma serine protease inhibitor that regulates tissue factor-induced blood coagulation. The cellular degradation of 125I-labeled TFPI (125I-TFPI) was inhibited more than 80% both by antibodies directed against LRP and by the LRP-associated 39-kDa protein, a protein that inhibits the binding and/or cell-mediated degradation of all ligands by LRP. Using rat hepatoma cells, we report that at 4 degrees C, 125I-TFPI binds to approximately 2 x 10(6) sites per cell with an equilibrium dissociation constant of approximately 30 nM. 125I-TFPI binding to the cell surface is not inhibited by the 39-kDa protein. Taken together, our results suggest that TFPI binds to an as-yet-unidentified cell surface molecule. After binding, LRP mediates the cellular degradation of TFPI.
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PMID:The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor. 751 57

1. Hormonal regulation of apolipoprotein E (apoE) gene expression by insulin and thyroid hormone was studied in a human hepatoma cell line, HepG2. 2. Changes at the mRNA level, mRNA translation, in vivo synthesis and secretion were monitored. 3. Both insulin and triiodothyronine were found to have no significant effect on apoE mRNA levels. 4. Insulin treatment caused an inhibition of: (a) the in vitro translation of endogenous apoE mRNA in a HepG2 cell-free system (25%), and (b) the incorporation of radioactivity into newly-synthesized apoE in an in vivo pulse-chase labeling experiment (32%). 5. Interestingly, apoE secretion rate was found to be significantly reduced with insulin (84%) suggesting that a major portion of newly-synthesized apoE may be shunted into a degradative pathway. 6. Using a similar experimental approach, triiodothyronine showed no significant effect on the rate of apoE synthesis or translation (6-15% decrease), however a slight reduction (20%) in secretion rate was shown. 7. Overall, apoE gene expression does not appear to be influenced by triiodothyronine significantly but is modulated by insulin at the translational and post-translational level.
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PMID:Hormonal regulation of human apolipoprotein E gene expression in HepG2 cells. 834 6

The uptake of triglyceride-rich lipoproteins has been described as being mediated by apolipoprotein E and lipoprotein lipase (LpL). Proteoglycans, the LDL-receptor, and the LDL receptor-related protein (LRP) are the cellular acceptors. In addition to LpL, hepatic lipase (HL) has been shown to bind to LRP. In this study, the role of HL in lipoprotein uptake was investigated. Human chylomicrons and rabbit beta-VLDL were used as ligands for human hepatoma cells, primary human hepalocytes, normal and proteoglycan-deficient Chinese hamster ovary (CHO) cells, and normal and LDL receptor-deficient human fibroblasts. We show that HL induces stimulation of the uptake of chylomicrons and beta-VLDL into the different cell lines. HL is known to bind to heparan sulfate, and experiments on normal and proteoglycan-deficient CHO cells showed that cell surface proteoglycans are essential for HL-mediated uptake of lipoproteins. To exclude LDL receptor-mediated uptake. we performed experiments on LDL receptor-deficient fibroblasts that demonstrated that the LDL receptor was not important for the HL-mediated uptake of lipoproteins. Crosslinking experiments confirmed the binding of HL to LRP on the cell surface. To identify the region of HL involved in the interaction with LRP, we used a C-terminal fragment of LpL, known to inhibit LpL-mediated uptake. HL-mediated lipoprotein uptake was suppressed by this fragment. Our experiments indicate that HL, like LpL, can mediate the uptake of lipoproteins into cells, most probably via a C-terminal binding site. The uptake, initiated by proteoglycan binding, is mediated by LRP.
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PMID:Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP). 872 46

In this work, we explored the existence of genetic variants within the apolipoprotein E gene transcriptional regulatory region, using a denaturing gradient gel electrophoresis screening of a region comprising nucleotides -1017 to +406. Upon a population study, three new polymorphic sites (-491, -427 and -219) and two mutations were found. Functional effects of the polymorphisms, assayed by transient transfection and electrophoretic mobility shift assays in a human hepatoma cell line, showed that polymorphisms at sites -491 and -219 of the APOE promoter produce variations in the transcriptional activity of the gene, most probably through differential binding of nuclear proteins.
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PMID:Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. 946 88

The effect of cytokines on apolipoprotein E (apo E) production and secretion was investigated in a human hepatoma cell line HepG2. Incubation of HepG2 cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF-alpha) for 48 h resulted in a significant dose-related decrease of apo E concentration in the culture medium, while intracellular apo E content increased without change in mRNA level. In contrast, IL-1 beta and TNF-alpha decreased both intracellular and medium apo A-I. Elution profiles of cholesterol and apolipoproteins revealed that apo E was present in apo E-rich high density lipoprotein (HDL) fraction and apo A-I was in apo E-rich HDL and small HDL fractions. IL-1 beta and TNF-alpha decreased both apo E and apo A-I in these fractions. The present results suggest that IL-1 beta and TNF-alpha suppress hepatic apo A-I expression and secretion but not expression of apo E, which could contribute to the abnormal lipid metabolism in certain cytokine-mediated inflammatory diseases.
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PMID:IL-1 beta and TNF-alpha suppress apolipoprotein (apo) E secretion and apo A-I expression in HepG2 cells. 961 72

Newly synthesized apolipoprotein E (apoE) is incompletely secreted and partially degraded by hepatocytes. To evaluate current models concerning apoE's role in remnant lipoprotein clearance by the liver, we performed a detailed and quantitative pulse-chase analysis of apoE secretion, subcellular distribution, and proteolytic degradation by the human hepatoma cell line HepG2. Only about 35% of newly synthesized apoE were found to be secreted to the culture medium. As determined by a protease-protection assay, a substantial amount of newly synthesized apoE was transported to the cell surface, constituting more than half of the cellular apoE under steady-state conditions. A subpopulation representing almost 40% of newly secreted apoE was rapidly rebound to the cell surface, indicating a dynamic equilibrium between cell surface and secreted apoE. These pools of newly synthesized apoE were subject to proteolytic turnover that occurred in lysosomes, presumably after re-endocytosis. We found that the proteolytic turnover of cell surface and secreted apoE was regulated by the availability of apoE ligands, being almost completely suppressed by the presence of lipoprotein-containing human serum or isolated lipoproteins, namely LDL and HDL. The characteristics of regulated degradation of cell surface apoE shed new light on potential physiological functions of this pool of apoE. Our results provide evidence that hepatocytes are capable of forming a large pool of cell surface-associated apoE, thereby supporting the previously proposed secretion-recapture model for apoE.
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PMID:Regulated turnover of a cell surface-associated pool of newly synthesized apolipoprotein E in HepG2 cells. 986 48

Liposome uptake by HepG2 human hepatoma cells was investigated in comparison with the uptake by J774 murine macrophage-like cells. HepG2 cells accumulated liposomes (egg yolk phosphatidylcholine (EPC)/Chol; 75/25, diameter 0.2 micron) at 37 degrees C comparably to J774 macrophage-like cells. Confocal microscopic observations revealed that J774 cells internalized EPC/Chol liposomes efficiently but HepG2 cells kept most of the liposomes bound on their plasma membrane surfaces. Poly(ethylene glycol) (PEG)-coated liposomes (0.2 micron) containing poly(ethylene glycol) cholesteryl ether (PEG-Chol) avoided cellular uptake at 37 degrees C by either cell line. In both cell lines, binding of PEG-coated liposomes was lower than that of EPC/Chol liposomes when incubation was carried out at 4 degrees C. To analyze the binding process at 37 degrees C, surface-bound liposomes were removed from the cells by pronase treatment. A reduction of the amount of bound-liposomes on cell surfaces was observed in the case of PEG-coated liposomes. Therefore, PEG-coating reduces direct binding of liposomes to the cell surfaces. The presence of apolipoprotein E (apoE) increased the uptake to EPC/Chol liposomes via its receptor in both cell lines. In contrast, cellular uptake of PEG-coated liposomes was not enhanced by treatment with apoE. Therefore, while apoE-mediated liposome uptake occurs in the case of EPC/Chol liposomes, it does not occur for PEG-coated liposomes; PEG-coating also inhibits protein-mediated binding to the cells. These results further imply that elusion from liver clearance of PEG-coated liposomes is not only due to the reduction of uptake by Kupffer cells but also by hepatocytes when liposomes are small enough to go through the fenestrates of the endothelial lining.
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PMID:Poly(ethylene glycol) derivative of cholesterol reduces binding step of liposome uptake by murine macrophage-like cell line J774 and human hepatoma cell line HepG2. 988 Sep 10

Both (R)- and (S)-3-hydroxy-13-methyltetradecanoic acids were prepared via a lipase-catalyzed enantioselective acylation. The total synthesis of N-4909 and its diastereomer were achieved by a coupling of either (R)- or (S)-3-hydroxy-13-methyltetradecanoic acid moiety with a hexapeptide moiety and by a cyclization with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and HOAt (1-hydroxy-7-azabenzotriazole) in a high dilution condition. The R configuration of 3-hydroxy-13-methyltetradecanoic acid was found to be important for stimulating the activity of apolipoprotein E secretion in human hepatoma Hep G2 cells.
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PMID:First total synthesis of N-4909 and its diastereomer; a stimulant of apolipoprotein E secretion in human hepatoma Hep G2 cells. 1034 69

Low density lipoproteins (LDL) contain apolipoprotein B-100 and are cholesteryl ester-rich, triglyceride-poor macromolecules, arising from the lipolysis of very low density lipoproteins. This review will describe the receptors responsible for uptake of whole LDL particles (holoparticle uptake), and the selective uptake of LDL cholesteryl ester. The LDL-receptor mediates the internalization of whole LDL through an endosomal-lysosomal pathway, leading to complete degradation of LDL. Increasing LDL-receptor expression by pharmacological intervention efficiently reduces blood LDL concentrations. The lipolysis stimulated receptor and LDL-receptor related protein may also lead to complete degradation of LDL in presence of free fatty acids and apolipoprotein E- or lipase-LDL complexes, respectively. Selective uptake of LDL cholesteryl ester has been demonstrated in the liver, especially in rodents and humans. This activity brings five times more LDL cholesteryl ester than the LDL-receptor to human hepatoma cells, suggesting that it is a physiologically significant pathway. The lipoprotein binding site of HepG2 cells mediates this process and recognizes all lipoprotein classes. Scavenger receptor class B type I and CD36, which mediate the selective uptake of high density lipoprotein cholesteryl ester, are potentially involved in LDL cholesteryl ester selective uptake, since they both bind LDL with high affinity. It is not known whether they are identical to the uncloned lipoprotein binding site and if the selective uptake of LDL cholesteryl ester produces a less atherogenic particle. If this is verified, pharmacological up-regulation of LDL cholesteryl ester selective uptake may become another therapeutic approach for reducing blood LDL-cholesterol levels and the risk of atherosclerosis.
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PMID:Low density lipoprotein uptake: holoparticle and cholesteryl ester selective uptake. 1053 83

Analogs of N-4909 (1), which had a stimulating activity for apolipoprotein E (apo E) secretion in Human hepatoma Hep G2 cells, were prepared and their activities examined. Cyclic analogs which had different kinds of amino acids or different number of amino acids from N-4909 (1) showed less effect on apo E secretion from Hep G2 cells. The length of acyl chain was found to be an important factor for the activity. Shorter chain reduced the activity. Linear analogs were also prepared. One of their analogs, N-5849 (17), which had six amino acids was found to have strong activity.
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PMID:Synthesis of N-4909 analogs. Part I. A stimulant of apolipoprotein E secretion in human hepatoma G2 cells. 1121 4


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