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)

The human hepatoma cell line, HepG2, was cultured with 25 OH cholesterol, a potent inhibitor of HMG-CoA reductase, in order to examine the effect of the oxysterol on apo E synthesis and secretion. Treatment of cells with oxysterol (2.5 microM) resulted in a greater than 90% inhibition of HMG-CoA reductase activity and a 3-fold reduction in its cognate mRNA level. However, apo E mRNA level and secretion were not affected after 24 h of drug treatment. This drug treatment was associated with a reduction in both cellular free and esterified cholesterol levels by 50% and 40%, respectively. Exposure of HepG2 cells to an ACAT inhibitor, the Sandoz compound (58-035) for 24 h, at a concentration of 5 micrograms/ml, resulted in a 30% increase and 70% decrease in the intracellular levels of free and esterified cholesterol, respectively. Under this regimen of drug treatment, the level of apo E mRNA was increased by approximately 70%, while HMG-CoA reductase mRNA level was decreased by 35%. When the cells were exposed to the combination of the ACAT inhibitor and 25 OH cholesterol, the cellular levels of free and esterified cholesterol were reduced by 30% and 80%, respectively. This combination of drugs had no effect on apo E mRNA; however, the level of HMG-CoA reductase mRNA was decreased by 3.5-fold. Taken together, the data suggested that reduction in the intracellular levels of either free or esterified cholesterol had no effect on apo E mRNA level. By contrast, a small increment in cellular free cholesterol content was associated with a significant induction in apo E mRNA level. Furthermore, 25 OH cholesterol caused a significant redistribution (50%) of apo E from the HDL fraction to the d greater than 1.21 g/ml infranatant. By using high performance liquid chromatography and molecular sieve columns, it was found that the appearance of a lipid-poor apo E particle was not an artifact of ultracentrifugation. This particle contained 85 wt% protein and 15 wt% of free cholesterol and phospholipid. The results suggested that a lipid-poor apo E particle was secreted by the HepG2 cells under certain circumstances.
Atherosclerosis 1992 Aug
PMID:The effect of 25-hydroxycholesterol on the regulation of apolipoprotein E mRNA levels and secretion in the human hepatoma HepG2. 132 83

U-73482, a novel acylCoA:cholesterol acyltransferase (ACAT) inhibitor with systemic activity, has been evaluated for its effects on a variety of lipid metabolic parameters in the rat. The compound inhibits ACAT in vitro in cultured Fu5AH rat hepatoma cells and demonstrates systemic activity through inhibition of hepatic ACAT in rats receiving the drug orally. U-73482 also lowers plasma triglycerides at 40 mg/kg per day in the rat and elevates high density lipoprotein cholesterol (HDL-chol) in a dose-related fashion over the range of daily intakes of 0-40 mg/kg in the rat. Elevations in HDL-chol are followed by elevations in total plasma cholesterol in normal rats but the compound exerts hypocholesterolemic activity in cholesterol-fed rats and promotes clearance of stored hepatic sterol in rats pretreated with a hypercholesterolemic diet and then changed over to normal chow. The triglyceride-lowering and HDL-chol elevating effects of U-73482 coupled with its ability to promote tissue sterol clearance and block the hypercholesterolemic effects of dietary cholesterol in animals, suggests that the compound has potential as a therapeutic agent for treatment of lipid disorders in man.
Atherosclerosis 1992 Feb
PMID:U-73482: a novel ACAT inhibitor that elevates HDL-cholesterol, lowers plasma triglyceride and facilitates hepatic cholesterol mobilization in the rat. 163 44

Regulation of expression of the genes for the low density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) is of central importance in the control of cholesterol metabolism and thus in influencing the concentration of low density lipoprotein in the plasma. This can be studied by investigating the effects of factors (hormones, drugs, etc.) on the levels of mRNA for these genes. An RNase protection assay is reported for measurement of the levels of mRNA for the LDLR and HMGR. Several probes have been developed for these genes, together with probes for the "housekeeping" genes, beta-actin and glyceraldehyde-3-phosphate dehydrogenase. Various conditions in the assay have been examined and optimised, e.g. conditions for solution hybridization and RNase digestion and the use of "sense" RNA standards. The assay allows accurate measurement of approximately 2 x 10(7) copies of LDLR and HMGR mRNAs, which is equivalent to the number of copies present in approximately 1 x 10(6) human dermal fibroblasts and approximately 5 x 10(5) Hep G2 liver hepatoma cells cultured in 10% fetal calf serum. The average number of copies of mRNA per cell was estimated in fibroblasts and Hep G2 cells under various conditions of regulation of the LDLR and revealed the following: [table: see text] Under the chosen conditions 10 copies per cell was the detection limit for the assay. The effect of these treatments on the number of copies of mRNA per cell for beta-actin and glyceraldehyde-3-phosphate dehydrogenase was also determined.
Atherosclerosis 1991 Sep
PMID:A sensitive RNase protection assay for the quantitation of the mRNAs for the LDL receptor and HMG-CoA reductase in human total RNA. Effects of treatments on cells in culture designed to up- and down-regulate expression of the LDL receptor. 182 10

Serum low-density lipoprotein (LDL) concentration is a major determinant of susceptibility to the development of atherosclerosis. A major component of the protein moiety of LDL and its precursor very-low-density lipoprotein is apolipoprotein B (apo B). The human hepatoma cell line, Hep G2, was used as a model for the investigation of mechanisms which control hepatic secretion of the apo B and lipid components of lipoproteins. Using a sensitive immunoradiometric assay for apo B developed in this laboratory, we showed that bovine serum albumin inhibited and glucose, and fatty acids enhanced the rate of accumulation of apo B in the culture medium of Hep G2 cells. However, these substances did not necessarily affect LDL lipids in the same way as apo B. This finding appeared to be due to Hep G2 cells expressing lipase activities which led to triacylglycerol and phospholipid hydrolysis and lipid reuptake. Reuptake of apo B also occurred, but its rate of accumulation in the culture medium suggested it was a closer reflection of its true secretory rate.
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PMID:Lipoprotein secretion by the human hepatoma cell line Hep G2: differential rates of accumulation of apolipoprotein B and lipoprotein lipids in tissue culture media in response to albumin, glucose and oleate. 195 47

Through a series of biological and analytical procedures, we demonstrate that a compound purchased from a commercial supplier as [7-3H]cholesterol was not cholesterol. In mouse peritoneal macrophages, this compound was metabolized differently than other radiolabeled cholesterol preparations and was accumulated in the steryl ester pool. In contrast, Fu5AH rat hepatoma cells did not discriminate this compound from cholesterol. Further analysis of the anomalous [7-3H]cholesterol by TLC after cholesterol oxidase treatment and by HPLC indicated that this radiochemical was less polar than cholesterol standard and other radiolabeled cholesterol preparations tested. Mass spectrometry analysis disclosed that the chemical has a similar fragmentation pattern and the same molecular weight (386) as cholesterol.
Atherosclerosis 1990 Oct
PMID:Potential problems in the use of commercial preparations of radiolabeled cholesterol. 228 4

This review on the risks and benefits of oral contraceptives clarifies the risks and misperceptions, and discusses 10 potential health benefits. In the U.S. where maternal mortality is about 20.6/100,000, the risk of death from pills ranges from 1.8 for nonsmokers to 6.5 for smokers. It is likely that most of the small existing mortality risk of pill use is due to thromboembolism. Atherosclerosis, the major cause of death for U.S. women, may be reduced by the pill. It is still controversial whether pills increase risk of hepatocellular carcinoma and malignant melanoma; they protect against endometrial cancer (the 3rd greatest cancer killer) and ovarian (the 4th) cancer; they may increase risk slightly in some subgroups for breast and cervical cancer, although data are conflicting. Pills also protect against ectopic pregnancy, benign breast disease, pelvic inflammatory disease, ovarian cysts, iron deficiency anemia and possibly uterine fibroids and osteoporosis. It is no longer held that orals protect against toxic shock syndrome or rheumatoid arthritis. It is estimated that oral contraceptives avert 50,000 hospital admissions per year in the U.S.
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PMID:The health effects of oral contraceptives: misperceptions, controversies, and continuing good news. 266 76

The rat H-35 cultured hepatoma cell line expresses receptors for homologous lipoproteins. In previously reported experiments distinct receptors were identified for chylomicron remnants, HDL and LDL, by direct binding studies that yielded distinctive binding constants, cross competition assays, and by differential inhibitory effects of EDTA and suramin. In the present experiments, the regulation of expression of these receptors was assessed by growing cells either in the presence or absence of lipoproteins in the media and by growing cells to different densities (50-800 micrograms cell protein/dish). LDL binding to cells was increased by lipoprotein deprivation at all cell densities. LDL binding was inversely related to cell density when cells were grown in lipoprotein deficient serum (LPDS) but cell density did not affect LDL binding by cells grown in newborn calf serum (NBCS). By contrast HDL binding was not appreciably different whether cells were grown in NBCS or in LPDS. However, HDL binding was inversely related to cell density by cells grown either in LPDS or in NBCS. Binding of chylomicron remnants was increased by growth in LPDS at all densities, but altering growth density in either culture medium had little effect on the cellular binding of chylomicron remnants. The distinctive effects of these experimental perturbations on the binding of the 3 lipoprotein classes tend to confirm the presence of 3 separate receptor activities. The experiments also demonstrate that the responses at least of some of the receptors of the hepatoma cells in culture resemble those of hepatocytes in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1988 Jan
PMID:Regulation of lipoprotein receptors on a rat hepatoma cell line. 283 82

The catabolism of low-density lipoproteins (LDL), the major cholesterol-carrying lipoproteins in plasma, is mediated in part via a high-affinity uptake pathway in the liver. Non-enzymatic glucosylation of lysine residues of apolipoprotein B, the major protein of LDL, blocks receptor-mediated uptake of LDL by fibroblasts and endothelial cells. We investigated the effect of the degree of glucosylation on the binding, uptake and degradation of radioiodinated LDL by the human hepatoma cell line Hep G2. Human LDL was glucosylated with 250 mM glucose and 30 mM cyanoborohydride at 37 degrees C. Incubations ranging from 3 to 48 h in duration resulted in the formation of 6-27% of glucitol-lysine adducts as demonstrated by coincubation with [14C]glucose. The degree of glucose incorporation corresponded to the extent of inhibition of binding, uptake and degradation of LDL (10-90%). The data are consistent with the view that glucosylation of LDL markedly impairs their catabolism. This phenomenon may be related to the pathophysiology of the premature atherosclerosis observed in diabetes mellitus.
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PMID:Impaired hepatocyte binding, uptake and degradation of glucosylated low-density lipoproteins. 301 18

The consumption of long chain polyunsaturated fatty acids by fish oils leads to profound lowering of plasma triacylglycerol but not of plasma cholesterol. Reasons for this were investigated with the human hepatoma cell line, the Hep G2 cell. Incubations with oleic acid (18:1 n9), linoleic acid (18:2 n6) and the characteristic marine fatty acid eicosapentaenoic acid (EPA, 20:5 n3) enriched cellular triacylglycerol mass, though least with EPA. However, secretion of very low density lipoprotein (VLDL) triacylglycerol and apoprotein B (measured by formation from [3H]glycerol and [3H]leucine) was markedly inhibited by EPA. Preincubation with linoleic acid reduced VLDL triacylglycerol but not apo B secretion in comparison with oleic acid which stimulated both. A possible effect on low density lipoprotein (LDL) removal was studied by measuring [125I]LDL binding. Preincubation with either EPA or linoleic acid inhibited the saturable binding of LDL, observed with oleic acid and control incubations. The binding of lipoproteins containing chylomicron remnants was not affected by any of the fatty acids.
Atherosclerosis 1987 Apr
PMID:Eicosapentaenoic acid inhibits the secretion of triacylglycerol and of apoprotein B and the binding of LDL in Hep G2 cells. 303 33

The binding of 125I-HDL obtained from nephrotic rats (HDLne) containing only apo A-I and apo C, to rat hepatoma cells (Fu5AH) grown to confluency was studied under conditions which increased the free cholesterol or the cholesteryl ester content. The high affinity binding (Kd = 5 nM) measured at 4 degrees C was unchanged. This transformed cell line also exhibited greater specificity for rat HDL compared to human HDL than has been reported for other types of cultured cells. When the cells were allowed to internalize and degrade HDLne at 37 degrees C, the acid-soluble products were derived almost entirely from the breakdown of apo A-I. Competition experiments with an LDL fraction from nephrotic rat plasma (LDLne) which contained 20% of apo A-I indicated that it was as effective as other rat HDL preparations in competing for the binding of HDLne at 4 degrees C, based on its content of apo A-I. Control experiments indicated that labeled apo A-I in HDLne exchanged less than 1% when incubated with a 50-fold excess of unlabeled LDLne for 2 h at 4 degrees C. These results point to a critical role of cell type in HDL binding. They support the view that apo A-I is a ligand. The up-regulation of high affinity HDL binding by cholesterol which has been reported with cultured human fibroblasts and Hep G2 cells does not occur in the Fu5AH rat hepatoma cell line.
Atherosclerosis 1987 Oct
PMID:High density lipoprotein binding by rat Fu5AH hepatoma cells is not related to cholesterol content. 311 94


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