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)

Alterations in plasma lipoprotein lipid and apoprotein accompanying the hyperlipidemia of rats bearing Morris hepatoma 7288C were characterized. In tumor-bearing animals all plasma lipid classes except cholesterol ester (CE) were elevated, particularly free cholesterol (FC) and triglyceride (TG), which increased by 57 and 63%, respectively. Fasting only partially reduced the tumor-induced hyperlipidemia and had no effect on the ratios of FC/CE and TG/CE. Analysis of plasma lipoproteins revealed an elevation of VLDL, IDL, and LDL in host rats, with more than a 2-fold increase in both lipid and protein of VLDL. In contrast, the three high density fractions, HDL2, HDL3, and d greater than 1.21 g/ml, were reduced. The inverse changes in concentration of host lipoproteins of lower versus higher density indicate a defective catabolism of TG-rich lipoprotein. This possibility is supported by the analysis of apolipoprotein. The percentage of total apoprotein contributed by apo C-I and C-II was reduced in all host fractions except HDL2, while the C-IIIs remained unchanged except for a small decrease in C-III-3 of host VLDL and a slight increase in the combined C-IIIs of HDL2. These changes were reflected in the decreased C-I+C-II/C-III ratios of all host lipoprotein fractions. Apo E levels remained similar to control values except for a significant decrease in HDL2. Host VLDL showed increased apo A-IV and A-I content, while A-IV was decreased in HDL2. Changes in apo B profiles were also observed.
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PMID:Characterization of alterations in plasma lipoprotein lipid and apoprotein profiles accompanying hepatoma-induced hyperlipidemia in rats. 394 72

Serum apoprotein A-I and A-II levels were determined by electroimmunoassay in patients with liver diseases and cholestasis. Significant decreases in apoprotein A-I and A-II levels were observed in such patients. The decreases were especially pronounced in the early phase of acute hepatitis and cholestasis. The decreases in A-II levels were more prominent than the decreases in A-I in severe hepatic dysfunction or cholestasis. Accordingly, the A-I/A-II ratio showed no change in the convalescent phase of acute hepatitis or chronic hepatitis but increased significantly in the early phase of acute hepatitis, cirrhosis of the liver, hepatoma, and cholestasis. The results suggested the existence of a high density lipoprotein with an abnormal apoprotein composition or a more profound decrease of HDL3 than of HDL2 in severe hepatocellular dysfunction of cholestasis.
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PMID:Serum apoprotein A-I and A-II levels in liver diseases and cholestasis. 627 23

Lipids of HDL (high density lipoproteins) and their subfractions (HDL2 and HDL3), and LCAT activity (lecithin: cholesterol acyltransferase) were determined in hepatobiliary diseases without severe hyperbilirubinemia (less than 10 mg/dl). The decrease in major lipid constituents (cholesterol and phospholipids) of HDL was mainly attributable to the decrease in those of HDL3, except in some liver diseases of acute or severe stage (acute hepatitis in an acute stage and hepatoma) which were accompanied with a simultaneous moderate decrease in those of HDL2 and in fatty liver which showed a preferential decrease in those of HDL2. The LCAT activity also decreased in several diseases. Some of the hepatobiliary diseases, on the contrary, showed an increase in HDL-triglycerides (mostly in HDL3 and in some diseases also in HDL2) which might participate to some extent in secondary hyperlipidemia in the liver parenchymal diseases, although they were the minor lipid constituents of HDL. From results that HDL3- but not HDL2-cholesterol levels significantly correlated with serum total protein, albumin and choline esterase, it was suggested that the decrease in large constituents of HDL, particularly of HDL3, is caused by hepatocellular dysfunction which causes inhibition of protein and lipid syntheses in the liver in most of the hepatobiliary diseases except for fatty liver which has a preferential decrease in HDL2 lipids.
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PMID:Changes in high density lipoproteins in patients with hepatobiliary diseases. Levels and lipid composition of HDL2 and HDL3 and LCAT reaction. 685 43

The influence of apolipoproteins (apo) A-I and A-II on the ability of high density lipoproteins (HDL) to remove cholesterol from cultured Fu5AH rat hepatoma cells was studied independently on alterations in the overall structure and lipid composition of the lipoprotein particles. To this end, apoA-I was progressively replaced by apoA-II in ultracentrifugally isolated HDL3 without inducing changes in other remaining lipoprotein components. As apoA-II was progressively substituted for apoA-I in HDL3 (A-II:A-I+A-II percentage mass: 29.5, 47.6, 71.5, 97.4, and 98.9%), the rate of cholesterol efflux from Fu5AH hepatoma gradually and significantly decreased after 2 or 4 h of incubation at 37 degrees C (cholesterol efflux: 30.4 +/- 0.8, 24.1 +/- 1.0, 19.8 +/- 1.2, 15.7 +/- 1.4, and 13.4 +/- 1.3%/2h, respectively; 38.4 +/- 1.5, 29.2 +/- 0.9, 27.0 +/- 0.2, 20.4 +/- 0.4, and 17.5 +/- 1.0%/4h, respectively) (p < 0.01 with all A-II-enriched HDL3 fractions as compared with non-enriched homologues). In agreement with data obtained with total HDL3, increasing the A-II:A-I+A-II percentage mass in HDL3 particles containing initially only apoA-I (HDL3-A-I) progressively reduced cellular cholesterol efflux. After 2 h of incubation, cholesterol efflux correlated negatively with A-II:A-I+A-II percentage mass (r = -0.86; p < 0.0001; n = 20), but not with either free cholesterol:phospholipid ratio, A-I+A-II:total lipid ratio or mean size of HDL3. As determined by using Spearman rank correlation analysis, the A-II:A-I+A-II% mass ratio correlated negatively with the apparent maximal efflux (Vmax(efflux)) (rho = -0.68; p < 0.05, n = 10), but not with the HDL3 concentration required to obtain 50% of maximal efflux (Km(efflux)) (rho = -0.08; not significant, n = 10). It was concluded that the apoA-I and apoA-II content of HDL3 is one determinant of its ability to promote cholesterol efflux from Fu5AH rat hepatoma cells.
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PMID:Modulation of cholesterol efflux from Fu5AH hepatoma cells by the apolipoprotein content of high density lipoprotein particles. Particles containing various proportions of apolipoproteins A-I and A-II. 776 92

The effect of oxysterols on efflux of cholesterol from mouse L-cell fibroblasts, rat Fu5AH hepatoma cells, J774 macrophages, and human EA.hy 926 endothelial cells was studied. Cells were preincubated with 25-hydroxycholesterol (25-OHC) either during labeling of the cells with [3H]cholesterol or during equilibration after labeling. Subsequently, the release of [3H]cholesterol into medium containing 0.2 mg HDL3/ml was measured and the fractional release of cellular [3H]cholesterol was calculated. Pretreatment with 25-OHC (1 microgram/ml) caused a 30% reduction in [3H]cholesterol efflux from L-cells during 8 h of incubation with HDL3. 25-OHC also inhibited cholesterol efflux from Fu5AH and J774 cells, but the effect was less marked. There was only a small, nonsignificant reduction of efflux from EA.hy 926 cells. The mechanisms of 25-OHC-induced inhibition of cellular cholesterol efflux was further studied in L-cells, because of their sensitivity to 25-OHC treatment. The effect of 25-OHC on cholesterol efflux was dose-dependent, with significant effects seen at 25-OHC concentrations as low as 50 ng/ml. The half-time for cholesterol efflux from 25-OHC-treated cells (5 micrograms/ml) was 13.0 +/- 3.3 h compared to 5.7 +/- 1.0 in control cells, corresponding to a 55% reduction in the rate of cholesterol release. Other oxysterols, including 7-ketocholesterol, 7 alpha- and 7 beta-hydroxycholesterol, and 22(S)-hydroxycholesterol also inhibited [3H]cholesterol efflux from L-cells significantly, but to a lesser degree. 25-Hydroxycholesterol (5 micrograms/ml) reduced efflux from both normal and cholesterol-enriched cells by 31 and 14%, respectively. Inhibition of efflux was similar when reconstituted HDL3-apolipoprotein/phosphatidylcholine particles or small unilamellar phosphatidylcholine vesicles were used as cholesterol acceptors instead of HDL3. The content of phospholipids, cholesterol and the FC/PL ratio of intact cells and from isolated plasma membrane vesicles were the same for control and 25-OHC-treated cells. Efflux of [3H]cholesterol from plasma membranes isolated from 25-OHC-treated cells was 20% less than efflux from membranes from control cells. The difference in efflux observed in intact cells is partially explained by the reduction in efflux from the plasma membrane. In conclusion, our studies suggest that oxysterols, especially 25-hydroxycholesterol, can reduce cellular cholesterol efflux in vitro. Therefore oxysterols, either endogenous or derived from the diet, may influence cellular cholesterol efflux in vivo, the first step in reverse cholesterol transport.
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PMID:Inhibition of cellular cholesterol efflux by 25-hydroxycholesterol. 777 62

Selective uptake of high-density lipoprotein (HDL) cholesteryl esters without parallel uptake of HDL apolipoproteins occurs by a non-endocytotic pathway that results in net delivery of cholesteryl esters to cells. With respect to the cellular mechanism of this pathway, previous studies with adrenal cells showed a cholesteryl ester pool that is reversibly associated with cells and which appears to mediate irreversible selective uptake. A cholesteryl ester pool with similar properties was observed in plasma membranes isolated from adrenal cells, suggesting that this is the site of the cellular pool. Human Hep G2 hepatoma cells also selectively take up HDL cholesteryl esters. Therefore we asked if these cells have a reversibly cell-associated cholesteryl ester pool as well that could mediate irreversible selective uptake. To do this, human HDL3 (d = 1.125-1.21 g/ml) was labeled in both its protein and cholesteryl ester moieties. Uptake of HDL3 tracers by Hep G2 cells was then studied. After an uptake incubation in the presence of labeled HDL3, either cellular uptake of tracers was immediately determined or cells were 'chase' incubated in the presence of unlabeled HDL before determination of cellular tracer content. Hep G2 cells selectively took up HDL3 cholesteryl esters under these conditions. However, a fraction of cholesteryl ester tracer selectively taken up was chased from the cells by subsequent incubation in the presence of unlabeled HDL. This reversible pool of cholesteryl ester tracer was distinct from that irreversibly internalized, and in excess of that accounted for by dissociation of labeled HDL3 particles bound to the cell surface. Selective uptake was down-regulated by prior incubation with LDL, and cholesteryl ester tracer in the reversible pool was down-regulated in parallel. Plasma membranes were isolated from Hep G2 cells and incubated with doubly labeled HDL3. HDL3 particles bound to these membranes, as indicated by the apolipoprotein tracer. However, HDL cholesteryl esters associated with plasma membranes in excess on that accounted for by HDL3 particles. This selective association of HDL3 cholesteryl ester tracer with membranes was reversible, and the tracer was chased during incubation in the presence of unlabeled HDL. These results suggest that, as with steroidogenic cells, a reversible pool of cholesteryl esters localized in the plasma membrane is involved in selective uptake of HDL3 cholesteryl esters by hepatic cells at a step prior to irreversible internalization.
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PMID:A pool of reversibly cell-associated cholesteryl esters involved in the selective uptake of cholesteryl esters from high-density lipoproteins by Hep G2 hepatoma cells. 838 60

High-density lipoprotein (HDL) cholesteryl esters are taken up by hepatocytes without parallel uptake of HDL apolipoproteins. This selective uptake of HDL cholesteryl esters is mediated by a non-endocytotic mechanism. Recently, selective uptake of cholesteryl esters also from low-density lipoprotein (LDL) was demonstrated. In this study, the role of the plasma membrane in selective uptake by the liver was investigated. Plasma membranes were prepared from rat liver or from human Hep G2 hepatoma cells. Human HDL3 (d = 1.125-1.21 g/ml) was either radioiodinated or labeled with [3H]cholesteryl oleate. Human low-density lipoprotein (d = 1.019-1.05 g/ml) was labeled in its protein and in its lipid moiety as well. Labeled lipoproteins, unlabeled lipoproteins and membranes were incubated. After separation by ultracentrifugation, apparent lipoprotein particle association with membranes was determined. Plasma membranes from rat liver and Hep G2 cells bound 125I-HDL3, indicating specific HDL3 particle binding. With both types of membrane, apparent HDL3 particle association according to [3H]cholesteryl oleate-labeled HDL3 was in significant excess on that due to 125I-HDL3. This indicates selective, i.e., particle binding independent, association of cholesteryl esters with the membrane. Excess unlabeled HDL3 competed for selective association, indicating a specific process. Selective association of HDL3 cholesteryl esters was concentration-, time-, temperature-dependent; however, parameters differed from HDL3 particle binding. HDL3 was modified by nitration; this modification inhibited HDL3 particle binding in contrast to unchanged selective association. These results suggested distinct membrane sites for HDL3 particle binding and selective cholesteryl ester association. Regulation of selective association was investigated. Hep G2 cells were cholesterol-loaded or cholesterol-depleted. Cellular cholesterol-loading down-regulated selective association of HDL3 cholesteryl esters with isolated membranes prepared from these cells. In parallel, selective uptake of HDL3 cholesteryl esters by Hep G2 cells was down-regulated in cholesterol-loaded cells. This parallel regulation of selective association with membranes and selective uptake by cells suggests a functional relationship. LDL, radiolabeled in its protein and in its lipid moiety, was incubated with liver plasma membranes. Besides LDL holo-particle receptor binding, also LDL cholesteryl esters were selectively associated with membranes. These data showed that selective association with membranes is not restricted to HDL but can occur from LDL as well. It is concluded that HDL3 as well as LDL cholesteryl esters can selectively be associated with hepatic plasma membranes, i.e., independent from particle binding. Results suggest an important role of the plasma membrane in the mechanism of selective cholesteryl ester uptake by the liver.
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PMID:Selective association of lipoprotein cholesteryl esters with liver plasma membranes. 844 47

1. We have recently reported that a short incubation (60 min) in vitro of high-density lipoprotein (HDL) 3 with human polymorphonuclear leucocytes (PMNs) leads to a proteolytic cleavage of apolipoprotein (apo) AII and to a change in the distribution of apo AI isoforms [Cogny, Paul, Atger, Soni and Moatti (1994) Eur. J. Biochem. 222, 965-973]. Since PMNs have been observed to be present in the earliest atherosclerotic lesions for a number of days, we investigated the HDL3 physiochemical modifications induced by in vitro interaction for a long period of time (24 h) with PMNs and the consequences of the changes on the ability of HDL3 to remove cholesterol from cells. 2. The stimulated PMN modification of HDL3 over 24 h resulted in a partial loss of protein with no variation in lipid molar ratio and a loss of 50% of HDL alpha-tocopherol content. The decrease in total protein was due first to a complete degradation of apo AII, and secondly to a partial loss of apo AI. The apo AI remaining on the particles was in part hydrolysed and the apo AI-1 isoform was completely shifted to the apo AI-2 isoform. These apo changes were accompanied by a displacement of the native HDL3 apparent size toward predominantly larger particles. 3. The ability of PMN-modified HDL3 to remove 3H-labelled free cholesterol from cells was measured in two cell lines: Fu5AH rat hepatoma cells and J774 mouse macrophages. HDL3 which had only a limited contact with PMNs (60 min) showed only a small non-significant reduction in the efficiency of cholesterol efflux. On the other hand, compared with native HDL3, HDL3 modified by PMNs for 24 h had a markedly reduced ability to remove cholesterol from cells, regardless of the type of cell. 4. The results suggest that PMN-modified HDL3, if occurring in vivo, could contribute to acceleration of the atherogenic process by decreasing the cholesterol efflux from cells.
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PMID:High-density lipoprotein 3 physicochemical modifications induced by interaction with human polymorphonuclear leucocytes affect their ability to remove cholesterol from cells. 866 Feb 96

In normal physiology, cells are exposed to cholesterol acceptors of different sizes simultaneously. The current study examined the possible interactions between two different classes of acceptors, one large (large unilamellar phospholipid vesicles, LUVs) and one small (HDL or other small acceptors), added separately or in combination to Fu5AH rat hepatoma cells. During a 24-hour incubation, LUVs of palmitoyl-oleoyl phosphatidylcholine at 1 mg phospholipid (PL) per milliliter extracted approximately 20% of cellular unesterified cholesterol (UC) label and mass in a slow, continuous fashion (half-time [t1/2] for UC efflux was approximately 50 hours) and human HDL3 at 25 micrograms PL per milliliter extracted approximately 15% cellular UC label with no change in cellular cholesterol mass (t1/2 of approximately 8 hours). In contrast, the combination of LUVs and HDL3 extracted over 90% of UC label (t1/2 of approximately 4 hours) and approximately 50% of the UC mass, indicating synergy. To explain this synergy, specific particle interactions were examined, namely, remodeling, in which the two acceptors alter each other's composition and thus the ability to mobilize cellular cholesterol, and shuttling, in which the small acceptor ferries cholesterol from cells to the large acceptor. To examine remodeling, LUVs and HDL were coincubated and reisolated before application to cells. This HDL became UC depleted, PL enriched, and lost a small amount of apolipoprotein A-I. Compared with equivalent numbers of control HDL particles; remodeled HDL caused faster efflux (t1/2 approximately 4 hours) and exhibited a greater capacity to sequester cellular cholesterol over 24 hours (approximately 38% versus approximately 15% for control HDL), consistent with their enrichment in PL. Remodeled LUVs still extracted approximately 20% of cellular UC. Thus, remodeling accounted for some but not all of the synergy between LUVs and HDL. To examine shuttling, several approaches were used. First, reisolation of particles after an 8-hour exposure to cells revealed that HDL contained very little of the cellular UC label. The label was found almost entirely with the LUVs, suggesting that LUVs continuously stripped the HDL of cellular UC. Second, bidirectional flux studies demonstrated that LUVs blocked the influx of HDL UC label into cells, while the rate of efflux of cellular UC was maintained. These kinetic effects explained the massive net loss of cellular UC to LUVs with HDL. Third, cyclodextrin, an artificial small acceptor that does not acquire PL and hence does not become remodeled, exhibited substantial synergy with LUVs, supporting shuttling. Thus, the presence of large and small acceptors together can overcome intrinsic deficiencies in each. Small acceptors are efficient at extracting cellular cholesterol because they approach cell surfaces easily but have a low capacity, whereas large acceptors are inefficient but have a high capacity. When present simultaneously, where the small acceptor can transfer cholesterol quickly to the large acceptor, high efficiency and high capacity are achieved. The processes responsible for this synergy, namely, remodeling and shuttling, may be general phenomena allowing cooperation both during normal physiology and after therapeutic administration of acceptors to accelerate tissue cholesterol efflux in vivo.
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PMID:Remodeling and shuttling. Mechanisms for the synergistic effects between different acceptor particles in the mobilization of cellular cholesterol. 908 95

In this study the effect of lipoprotein lipase (LPL) on the selective uptake of high density lipoprotein (HDL) cholesteryl esters (CE) by hepatic cells was investigated. Human HDL3 (d 1.125-1.21 g/ml) was radiolabeled with 125I in the protein moiety and with 3H in the CE moiety. LPL was prepared from bovine milk. Human hepatocytes in primary culture and human Hep3B hepatoma cells were incubated in medium containing doubly radiolabeled HDL3 with or without LPL. Without LPL, apparent HDL3 particle uptake according to the lipid tracer (3H) was in excess of that due to the protein label (125I) indicating selective CE uptake from HDL3. Addition of LPL increased selective CE uptake up to 7-fold. This stimulation of HDL3 selective CE uptake was independent of the lipolytic activity of LPL as suggested by several experimental approaches. Cell surface heparan sulfate proteoglycan deficiency decreased the LPL-mediated increase in selective CE uptake suggesting an important role for these molecules. In low density lipoprotein (LDL) receptor- or LDL receptor-related protein-(LRP)-deficient cells, LPL increased selective CE uptake as it did in normal cells yielding no evidence that these receptors play a role in the LPL effect on selective CE uptake. In summary, lipoprotein lipase increases the selective uptake of high density lipoprotein-associated cholesteryl ester by hepatic cells in culture. This effect is dependent on cell surface heparan sulfate proteoglycans but independent of lipolysis and of endocytosis mediated by low density lipoprotein receptor-related or low density lipoprotein receptors.
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PMID:Lipoprotein lipase mediates an increase in the selective uptake of high density lipoprotein-associated cholesteryl esters by hepatic cells in culture. 968 36


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