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)

High density lipoprotein (HDL) is thought to play a significant role in the process of reverse cholesterol transport. It has become clear that the apolipoprotein (apo) composition of HDL is important in determining the metabolic fate of this particle. The major proteins of human HDL are apoAI and APOAII; the latter protein is a disulfide-linked dimer in humans and higher primates but monomeric in the other species. The consequences of the apo Cys6-Cys6 disulfide bridge in apoAII for human HDL structure and function are not known. To address this issue, the influence of the Cys6-Cys6 disulfide bridge on the interaction of human apoAII with palmitoyl-oleoyl phosphatidylcholine has been studied. The size and valence of a series of homogeneous discoidal complexes containing either monomeric (reduced and carboxymethylated) or dimeric apoAII have been determined, and their ability to remove cholesterol from rat Fu5AH hepatoma cells grown in culture has been compared. The apoAII dimer and monomer form discoidal complexes of similar size, with twice as many of the latter molecule required per disc. Removal of the disulfide bond influences the stability of the helical segments around the edge of the disc as seen by a decrease in alpha-helix content of the monomeric protein. The discoidal particles containing the monomeric form of apoAII are somewhat more effective than particles containing either dimeric apoAII or apoAI in removing cellular cholesterol. Overall, reduction of the disulfide bridge of apoAII probably does not have a major effect in the determination of HDL particle size in vivo. It follows that the evolution of the Cys6-Cys6 disulfide bond in higher primates probably has not had a major effect on the function of the apoAII molecule.
 ...
PMID:Comparison of the structural and functional effects of monomeric and dimeric human apolipoprotein A-II in high density lipoprotein particles. 893 42

The pivotal role of apolipoprotein AI (Apo AI) in mediating reverse cholesterol transport has lead us to the study of transcription factors that influence the expression of this gene. Previous studies show that rat HNF-4 enhances the activity of a cis-acting site C in the rat Apo AI promoter. Since sites C and A share 80% homology, we have examined whether HNF-4 binds to and modulates the transcriptional activity of the A-motif. Results show that HNF-4 binds to site A. The transcriptional activity of site A in a human hepatoma cell line, HuH-7, increases 2-2.5-fold in the presence of antisense HNF-4, but the sense construct has no effect on the activity of the reporter template. The lack of an effect of HNF-4 on site A activity may be due to high endogenous levels of the factor in HuH-7 cells. However, in BHK cells HNF-4 clearly inhibits the transcriptional activity of site A. Together these findings suggest that in contrast to the enhancing effects of HNF-4 on site C, the same factor inhibits site A activity. Since hepatocytes normally contain the T3 receptor and this nuclear factor increases site A action, cotransfection of T3 receptor along with antisense HNF-4 further augments the activity of p5'A.CAT. In summary, rat HNF-4 binds to site A from rat Apo AI DNA, and this factor suppresses site A activity. HNF-4 interferes with the enhancer role of the T3 receptor and thus contributes negatively to the net expression of the Apo AI gene.
 ...
PMID:Hepatocyte nuclear factor 4 inhibits the activity of site A from the rat apolipoprotein AI gene. 900 81

We measured the capacity of human plasma to induce cholesterol efflux from Fu5AH rat hepatoma cells in four groups of men with or without non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD). Plasma from men with both NIDDM and CAD (n = 47) had the lowest efflux capacity (17.3 +/- 3.6%) whereas healthy control subjects with neither diabetes nor CAD (n = 25) had the highest capacity (19.8 +/- 3.4%). The groups with CAD but no diabetes (n = 44) and with NIDDM but no CAD (n = 35) had intermediate efflux values (18.5 +/- 3.8 and 18.5 +/- 3.9%, respectively). In a 2 x 2 factorial ANOVA, the differences were significant with respect to the presence of CAD (P = 0.038) and NIDDM (P = 0.041), with no interaction between the factors. The concentration of HDL particles containing apolipoprotein (apo) A-I but no apo A-II (LpA-I) was not related to efflux capacity in univariate or multivariate analyses. A multivariate regression analysis showed that when controlled for the presence of NIDDM and CAD, the concentration of particles containing both apo A-I and apo A-II (LpA-I:A-II) and plasma phospholipid transfer protein activity were both positively, independently, and significantly (P < 0.001) related to cholesterol efflux capacity.
 ...
PMID:Cholesterol efflux from Fu5AH hepatoma cells induced by plasma of subjects with or without coronary artery disease and non-insulin-dependent diabetes: importance of LpA-I:A-II particles and phospholipid transfer protein. 912 15

Using recombinant adenoviral vectors and a dominant negative mutant of HNF-4, we have examined the contribution of hepatocyte nuclear factor 4 (HNF-4) to endogenous apolipoprotein AI and CIII mRNA expression. Overexpression of HNF-4 leads to a 7.4-fold increase in apolipoprotein CIII expression, while infection with the dominant negative mutant of HNF-4 reduces the level of apolipoprotein CIII mRNA by 80%, demonstrating that endogenous HNF-4 is necessary for apolipoprotein CIII expression. Experiments using the hepatoma cell lines, HepG2 and Hep3B, indicate that HNF-4 is also involved in the regulation of apolipoprotein AI expression in these lines. However, the effect of HNF-4 on apolipoprotein AI expression is much more dramatic in cell lines derived from intestinal epithelium. Infection of the intestinal-derived cell line IEC-6 with the HNF-4 adenovirus resulted in a greater than 20-fold increase in the level of apolipoprotein AI mRNA. These results indicate that HNF-4 does regulate apolipoprotein AI and CIII mRNA expression and suggest that HNF-4 is critical for intestinal apolipoprotein AI expression.
 ...
PMID:Utilization of recombinant adenovirus and dominant negative mutants to characterize hepatocyte nuclear factor 4-regulated apolipoprotein AI and CIII expression. 915 49

The effect of oleic acid (OA), stearic acid (SA) and elaidic acid (EA) on cellular and secreted apolipoprotein (apo) B was examined in McArdle RH-7777 (McArdle) hepatoma cells and in primary rat hepatocytes. ApoB secretion by McArdle cells was significantly inhibited by 20% in 8 h incubations in medium containing EA and SA and by 50% in medium containing OA. In contrast, apo B secretion and cellular apo B of primary rat hepatocytes was relatively unaffected by incubations in medium containing fatty acids. Both B100 and B48 secretion in McArdle wild type and B48 in apo B mRNA editing enzyme catalytic polypeptide transfectants expressing B48 were inhibited to a similar extent indicating an effect of OA on both apo B species. The effect of OA occurred without changes in cellular apo B or in apo B mRNA abundance suggesting a post-transcriptional mechanism. Time course studies indicate that the suppressive effect of OA requires 4 h of incubation suggesting the depletion of a limiting factor important in apoB secretion. By increasing the proportion of palmitic acid to OA in the medium, apoB secretion by McArdle cells was progressively restored to control levels implicating an unique role for newly synthesized saturated fatty acid.
 ...
PMID:Effects of fatty acids on apolipoprotein B secretion by McArdle RH-7777 rat hepatoma cells. 923 86

The chicken hepatoma cell line LMH-2A, which permanently overexpresses the chicken estrogen receptor, was used to study the synthesis and secretion of lipoproteins in response to treatment with estrogen. In the absence of the hormone, only small amounts of apolipoprotein B (apoB) and no apolipoprotein VLDL II (apoII) were found in cell extracts. After treatment of cells with moxestrol, a stable estrogen derivative, for 24 to 48 h, a dramatic increase in the quantities of these lipoproteins was observed both in cell extracts and in the medium. As determined by pulse-chase experiments, both proteins also showed enhanced rates of synthesis after estrogen induction, and secretion of the newly synthesized proteins was essentially complete by 6 h. The secreted apoB-containing lipoprotein particles have a density corresponding to that of very low density lipoprotein (VLDL). Furthermore, in estrogen-stimulated cells, the secreted particles also contain apoII, as shown by co-immunoprecipitation of apoII, and apoB. It appears that vitellogenin, the product of another estrogen-regulated gene in egg-laying species, is not synthesized by LMH-2A cells. Taken together, the data suggest that LMH-2A cells provide a new and promising cell system to investigate lipoprotein synthesis, assembly, and secretion in an estrogen-dependent manner.
 ...
PMID:Estrogen dependence of synthesis and secretion of apolipoprotein B-containing lipoproteins in the chicken hepatoma cell line, LMH-2A. 925 58

C57BL/6 mice are susceptible to diet-induced atherosclerosis, whereas BALB/c mice are resistant. The susceptibility of C57BL/6 mice has been linked to decreased plasma HDL cholesterol in response to a diet containing fat, cholesterol, and cholic acid. Feeding C57BL/6 mice a diet consisting of fat and cholesterol, but no cholic acid, increased plasma high density lipoprotein (HDL) cholesterol. The increase in HDL was associated with increases in both plasma apolipoprotein (apo)A-I and hepatic apoA-I mRNA. Supplementation of the cholesterol-rich diet with cholic acid inhibited the stimulatory effect of cholesterol on hepatic apoA-I mRNA expression, resulting in similar hepatic apoA-I mRNA levels compared to chow-fed mice. Atherosclerosis-resistant BALB/c mice were also resistant to diet-induced changes in plasma HDL, apoA-I, and hepatic apoA-I mRNA levels. Previous studies showed that the diets changed both the activity and mRNA encoding the liver specific enzyme 7alpha-hydroxylase (1993.J. Lipid Res. 34: 923-931). In both strains of mice, hepatic expression of apoA-I and 7alpha-hydroxylase mRNA varied in parallel. Whereas susceptible C57BL/6 mice also showed a significant correlation between HDL cholesterol and expression of 7alpha-hydroxylase, no such correlation was observed in BALB/c mice, suggesting that genetic differences in HDL metabolism, not hepatic apoA-I synthesis, are responsible for the strain specific differences in plasma HDL levels. The finding that lecithin: cholesterol acyltransferase (LCAT) activity was significantly decreased in C57BL/6 mice, but not in BALB/ c mice fed the atherogenic diet, further supports this conclusion. Additional studies show that McArdle hepatoma cells stably expressing plasmid-derived rat 7alpha-hydroxylase recapitulated the parallel linear relationship between 7alpha-hydroxylase and apoA-I mRNA expression observed in both strains of mice. These data link hepatic apoA-I mRNA expression to hepatic cholesterol/bile acid metabolism.
 ...
PMID:Cholesterol 7alpha-hydroxylase influences the expression of hepatic apoA-I in two inbred mouse strains displaying different susceptibilities to atherosclerosis and in hepatoma cells. 925 69

Although L-triiodothyronine (L-T3) lowers cholesterol, this hormone is not used to treat hypercholesterolemia because of its cardiotoxic effects. Thyromimetics, such as the novel compound CGS 23425, that mimic the beneficial but lack the detrimental effects of T3, may be useful in the treatment of hypercholesterolemia. To show that CGS 23425 has no cardiotoxicity, atrial contractility and force were both measured and found to be unchanged in rats treated with up to 10 mg/kg drug. The lipid lowering actions of this drug resulted in a 44% decrease in low-density lipoprotein (LDL) cholesterol in hypercholesterolemic rats treated with 10 microg/kg of the compound. Normal rats required a higher dose of 1000 microg/kg to elicit a similar 50% reduction in LDL cholesterol. Both CGS 23425 or T3 (10 nM) increased the specific binding of 125I-labeled LDL to Hep G2 cells and increased LDL receptor number by 44 and 49%, respectively. These data indicate that CGS 23425 enhances hepatic clearance of serum LDL cholesterol. Normal and fat-fed animals treated with the drug showed a dose-dependent increase in apolipoprotein AI, a protein that promotes the efflux of cholesterol from peripheral tissues. Transient transfection of a rat apolipoprotein AI promoter-chloramphenicol acetyltransferase construct, in human hepatoma cells, showed a dose-dependent increase in chloramphenicol acetyltransferase activity with EC50 values of 2 x 10(-12) M and 10(-10) M for thyroid hormone receptors beta1 and alpha1, respectively, with maximal responses at 10(-7) M. These data indicate that CGS 23425 is a thyromimetic that increases apolipoprotein AI expression via thyroid hormone receptor. In summary, CGS 23425 ameliorates hypercholesterolemia by increasing apolipoprotein A1 and the clearance of LDL cholesterol. Therefore, a compound like CGS 23425 may be useful for the prevention and reversal of atherosclerosis.
 ...
PMID:Beneficial effects of a novel thyromimetic on lipoprotein metabolism. 928 17

In the preovulatory period, follicular fluid contains only HDL. Biochemical characterization of such lipoproteins showed that follicular fluid HDLs were cholesterol-poor particles compared with serum HDLs, whereas the amount of phospholipids, expressed as percent weight, was significantly higher in follicular fluid HDLs (28.5%) than in serum HDLs (25.0%, P < .05). The amount of apolipoprotein (apo) A-IV per apo A-I was significantly higher in follicular fluid than in serum (0.77 versus 0.58 mg/g apo A-I, P < .02). To explore the role of HDLs as cholesterol acceptors in physiological media, we compared the ability of either whole human follicular fluids or homologous sera to promote cellular cholesterol efflux using Fu5AH rat hepatoma cells. At equivalent concentrations of HDL cholesterol in follicular fluid and in serum, t1/2 values for cholesterol efflux were in the same range. In addition, estimated maximal efflux values were not significantly different in follicular fluid and serum (45.9% and 49.6%, respectively), as were K(m) values (0.064 and 0.071 mmol/L HDL cholesterol respectively). In addition, isolated HDLs displayed the same capacity to promote cellular cholesterol efflux in both media. Thus, the kinetics and dose-response data between these two physiological media showed that HDLs play the major role in cellular cholesterol efflux. The rate of cholesterol esterification, as measured in the presence of cells, was significantly higher in follicular fluid than in serum at constant HDL cholesterol concentrations, whereas the rate of esterified cholesterol transfer toward added LDL was lower. In contrast, in a cell-free system, lecithin:cholesterol acyltransferase activity represented only 26% of that in serum HDL, whereas cholesterol ester transfer protein activities were comparable. In summary, in this particular model, we confirmed the essential role of HDLs as physiological acceptors in the removal of cellular cholesterol.
 ...
PMID:Structural and functional comparison of HDL from homologous human plasma and follicular fluid. A model for extravascular fluid. 930 42

This study compared the structural and functional properties of glucosylated and non-glucosylated LpA-I particle subfractions (GLpA-I and NGLpA-I, respectively) isolated from patients with poorly controlled type 1 (insulin-dependent) diabetes. Compared with NGLpA-I, GLpA-I showed an enrichment in triglycerides (P < .05) and a depletion in phospholipid (P < .05) content. Moreover, the triglycerides-to-cholesteryl esters ratio was increased (P < .05), suggesting an increased cholesteryl ester transfer protein activity and a possible transport defect that accelerates atherogenesis. The surface-to-core constituents ratio, an indirect estimate of particles size, is lower in GLpA-I (P < .01) than in NGLpA-I, correlating well with a larger median size (P < .05) as seen by electron microscopy. The apolipoprotein (apo) A-I conformation was evaluated through determination of the immunological accessibility of three different domains defining specific epitopes for anti-apo A-I monoclonal antibodies. We observed a marked decreased accessibility for two of these regions, which interestingly have already been implicated in the interaction with cells. Cell culture data suggest that nonenzymatic glycosylation occurring on apo A-I can modify lipoprotein function, since it results in a decreased binding of GLpA-I to HeLa cells and impaired cholesterol efflux from Fu5AH rat hepatoma cells.
 ...
PMID:In vivo glucosylated LpA-I subfraction. Evidence for structural and functional alterations. 940 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>