| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Inhibition of acyl-CoA: cholesterol acyltransferase by isohalobacillin, a complex of novel cyclic acylpeptides produced by Bacillus sp. A1238 Hasumi, K., K. Takizawa, et al. (1995), J Antibiot (Tokyo) 48(12): 1419-24. Abstract: A complex of metabolites consisting of two isomeric cyclic acylpeptides was isolated from a culture of Bacillus sp. A1238 by successive chromatographies on Amberlite XAD-7, silica gel and silica ODS columns. By a combination of spectroscopic and chemical analyses, the two subcomponents were identified as isomers of halobacillin, and the complex was designated isohalobacillin. Each molecule of isohalobacillin subcomponents contains either a 3-hydroxy-1-oxo-13-methyltetradecyl or a 3-hydroxy-1-oxo-12 methyltetradecyl moiety in place of a 3-hydroxy-1-oxopentadecyl moiety that is found in the halobacillin molecule. In a cell-free assay, isohalobacillin inhibited acyl-CoA: cholesterol acyltransferase by 50% at a concentration of 50 microM. When added to a culture of macrophage J774, the agent inhibited oxidized low density lipoprotein-induced synthesis of cholesteryl ester from 14Coleate without affecting surface binding, internalization and degradation of the lipoprotein in the cells. |
| Inhibition of acyl-CoA: cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells Musanti, R., L. Giorgini, et al. (1996), J Lipid Res 37(1): 1-14. Abstract: There is evidence that the overproduction of apoB-100-containing lipoproteins by the liver is the underlying event in some forms of dyslipoproteinemia. This metabolic status is associated to an increased risk of developing premature coronary artery disease CAD. The conclusions from previous studies suggested that the availability to the hepatocytes of cholesterol that is readily esterified is an important determinant for VLDL and LDL secretion. In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100 secretion rate from a human hepatoma cell line (HepG2). When the specific ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of the cellular cholesteryl ester content and at the same time a significant reduction of the neutral lipids and of the apoB-100 secretion rate were noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml) caused a 4-fold increase of the cellular cholesteryl ester content and a 2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to 10-7 M) prevented the effects elicited by the oxysterol. On the contrary, lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of the lipid and of the apolipoprotein composition of the lipoproteins secreted in the medium revealed that ACAT inhibition had the dual effect of both decreasing the number of apoB-100-containing lipoproteins secreted as well as their cholesteryl ester load. Altogether, these data support the idea of a close relationship between ACAT activation, leading to increased cholesteryl ester availability, and apoB-100-containing lipoprotein secretion. It is speculated that ACAT inhibitors may prove useful for the treatment of human dyslipoproteinemias caused by the hepatic overproduction of apoB-100-containing lipoproteins. |
| Inhibition of acyl-CoA:cholesterol acyltransferase in Chinese hamster ovary (CHO) cells by short-chain ceramide and dihydroceramide Ridgway, N. D. (1995), Biochim Biophys Acta 1256(1): 39-46. Abstract: The biological activity of ceramide, an intermediate in the synthesis and catabolism of sphingolipids, has been shown to be mimicked by short-chain N-acyl analogues. A potential role for ceramide in modulating cholesterol esterification was investigated using a series of short-chain ceramides and dihydroceramides. Acyl-CoA:cholesterol acyltransferase (ACAT) in CHO cells was inhibited rapidly (< 30 min) and in a dose-dependent fashion by two N-acyl analogues of naturally occurring D-erythro-ceramide, N-acetyl-sphingosine (D-erythro-C2-ceramide) and N-hexanoyl-sphingosine (D-erythro-C6-ceramide). At 10 microM D-erythro-C2-ceramide, esterification of cholesterol was inhibited by 95% in CHO cells grown in delipidated serum, and 80-85% in cells grown in 25-hydroxycholesterol or human low-density lipoprotein (LDL). D-erythro-C2-Ceramide did not inhibit 14Coleate-labelling of triacylglycerol and phospholipid. Inhibition of cholesterol esterification in cells and isolated membranes required the D-erythro (2S,3R) configuration (the L-threo isomer of C2-ceramide was not inhibitory) and an N-acyl group (sphingosine and sphinganine did not inhibit). DL-erythro-C2-Dihydroceramide was also a potent ACAT inhibitor in isolated membranes (IC50 0.2 microM) and cells indicating lack of requirement for a 4-trans double bond. Consistent with results for C2-ceramides, DL-threo-C2-dihydroceramide was not inhibitory in cells or in vitro. Long-chain ceramide and N-palmitoyl-dihydroceramide did not inhibit ACAT in isolated membranes. Compared to D-erythro-C2-ceramide, D-erythro-C6- and C4-ceramide were slightly weaker inhibitors of ACAT in isolated membranes. Thus, N-acyl chain length could influence inhibition, either by altering the effective concentration of ceramide in membranes or affinity for the ACAT enzyme. Short-chain ceramides and dihydroceramides are the first ACAT inhibitors described with structural similarity to a naturally occurring compound. |
| Inhibition of acylcoenzyme A: cholesterol acyltransferase activity by PD128O42: effect on cholesterol metabolism and secretion in CaCo-2 cells Field, F. J., E. Albright, et al. (1991), Lipids 26(1): 1-8. Abstract: The regulation of cholesterol uptake and secretion by acylcoenzyme A:cholesterol acyltransferase (ACAT) was investigated in the human intestinal cell line, CaCo-2. A new ACAT inhibitor, PD128042 (CI-976), was first characterized. The addition of the fatty acid anilide to membranes prepared from CaCo-2 cells inhibited ACAT activity without altering the activities of HMG-CoA reductase, fatty acid Co-A hydrolase, or triglyceride synthetase. PD128042 was a competitive inhibitor of ACAT with 50% inhibition occurring at a concentration of 0.2 micrograms/mL. When added to the medium of CaCo-2 cells at a concentration of 5 micrograms/mL, PD128042 inhibited oleate incorporation into cholesteryl oleate by 92% and increased oleate incorporation into triglycerides and phospholipids by 51% and 38%, respectively. After incubating CaCo-2 cells with the ACAT inhibitor, the rate of newly synthesized cholesterol decreased by 75% and membranes prepared from these cells contained significantly less HMG-CoA reductase activity. PD128042 significantly decreased the basolateral secretion of newly synthesized cholesteryl esters without affecting the secretion of newly synthesized triglycerides or phospholipids. The inhibitor decreased the esterification of labeled exogenous cholesterol which was taken up by the cell from bile salt micelles. Moreover, after 16 hr of ACAT inhibition, less labeled unesterified micellar cholesterol was associated with the cell. The esterification of cholesterol in CaCo-2 cells plays an integral role in the uptake of cholesterol through the apical membrane and its eventual secretion at the basolateral membrane. |
| Inhibition of ADP-induced platelet aggregation by apoE is not mediated by membrane cholesterol depletion Riddell, D. R. and J. S. Owen (1996), Thromb Res 81(5): 597-606. Abstract: We have previously shown that plasma HDL-E, a minor subclass of high-density lipoproteins (HDL) containing apolipoprotein (apo) E, has a potent anti-platelet effect and implicated apoE as the active constituent. Recently, apoE complexes with phospholipids (DMPC) were reported to inhibit thrombin-induced aggregation by sequestering platelet membrane cholesterol. Here we demonstrate that platelet cholesterol depletion is an improbable explanation for the suppressive effect of apoE:DMPC on ADP-mediated platelet aggregation; only 0.5% of cholesterol was released prior to addition of ADP to initiate aggregation while lactoferrin, which does not accept cellular cholesterol, was also inhibitory. Previous studies have shown that apoE and lactoferrin are both bound by platelets but whether this provides the initial stimulus for suppression of aggregation remains to be established. |
| Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits Duverger, N., H. Kruth, et al. (1996), Circulation 94(4): 713-7. Abstract: BACKGROUND: Prospective epidemiological studies support the hypothesis that high levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I limit atherosclerosis development. However, more data from studies with animal models of atherosclerosis that resemble the human disease are required to demonstrate the effect of apo A-I in the inhibition of atherogenesis. The rabbit is a good animal model for human atherosclerosis. METHODS AND RESULTS: Human apo A-I-transgenic rabbits have been produced, and we have evaluated the effect of apo A-I on the development of atherosclerosis in transgenic rabbits fed a cholesterol-rich diet for 14 weeks. Plasma cholesterol levels of atherogenic apo B-containing lipoproteins were similar for transgenic and control rabbits (> 1000 mg/dL), while plasma levels of HDL cholesterol in the transgenic group were always about twice that of the control group (68 +/- 11 versus 37 +/- 3 mg/dL at 14 weeks; P <.001). At the end of the experiment, the amount of aortic surface area covered by lesions as well as the amount of lipid accumulation in the aorta were significantly less in transgenic rabbits compared with the control group (15 +/- 12% versus 30 +/- 8%, P <.0027 for the surface area of the thoracic aorta; 116 +/- 31 versus 247 +/- 39 mumol/g aorta, P <.0068 for cholesterol content in total aorta). CONCLUSIONS: Overexpression of human apo A-I in rabbits inhibits the development of atherosclerosis in this animal model that resembles, in many respects, human atherosclerosis. |
| Inhibition of biliary cholesterol and phospholipid secretion by cefmetazole. The role of vesicular transport and of canalicular events Cava, F., J. Gonzalez, et al. (1991), Biochem J 275 (Pt 3): 591-5. Abstract: A number of organic anions selectively inhibit the biliary secretion of cholesterol and phospholipids without affecting bile acid secretion. We studied the effect of cefmetazole, a third-generation cephalosporin, on biliary lipid secretion in the rat. Injection of cefmetazole at a dose of 200 mumol/kg body wt. induced a choleretic effect and a significant decrease in the biliary output of cholesterol and phospholipid, without changes in bile acid secretion. The decrease was more marked for cholesterol than for phospholipid secretion, with a significant decrease in their molar ratio in bile. The effects were apparently unrelated to an inhibition of intracellular vesicular transport because, after injection of horseradish peroxidase, both the time course and total amount secreted of the protein did not significantly differ between control animals and those receiving cefmetazole. The secretory rate of the lysosomal marker acid phosphatase was not affected by cefmetazole administration. Biliary outputs of the plasma-membrane enzymes alkaline phosphatase and gamma-glutamyltransferase were significantly decreased by the antibiotic. These results point to an effect of cefmetazole at the level of the canalicular membrane. |
| Inhibition of biliary phospholipid and cholesterol secretion by organic anions affects bile canalicular membrane composition and fluidity Verkade, H. J. (2000), J Gastroenterol 35(6): 481-5. |
| Inhibition of cellular cholesterol efflux by 25-hydroxycholesterol Kilsdonk, E. P., D. W. Morel, et al. (1995), J Lipid Res 36(3): 505-16. Abstract: 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 3Hcholesterol or during equilibration after labeling. Subsequently, the release of 3Hcholesterol into medium containing 0.2 mg HDL3/ml was measured and the fractional release of cellular 3Hcholesterol was calculated. Pretreatment with 25-OHC (1 microgram/ml) caused a 30% reduction in 3Hcholesterol 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 3Hcholesterol 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 3Hcholesterol 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. |
| Inhibition of certain strains of HIV-1 by cell surface polyanions in the form of cholesterol-labeled oligonucleotides Ahn, K. S., W. Ou, et al. (2004), Virology 330(1): 50-61. Abstract: Cholesterol-labeled oligonucleotides were found several years ago to inhibit HIV-1 in tissue culture at nanomolar concentrations. We present evidence that this is mainly due to an electrostatic interaction between polyanionic oligonucleotide concentrated at the cell surface and a positively charged region in the V3 loop of the HIV-1 envelope protein. When added to tissue culture, cholesterol-labeled oligonucleotides became concentrated at the plasma membrane and potently inhibited virus entry and cell fusion mediated by the envelope protein of some X4 strains of HIV-1, but had little effect on fusion mediated by R5 strains of HIV-1, amphotropic MLV envelope protein, or VSV-G protein. Noncholesterol-labeled oligonucleotides did not bind to the cell surface or inhibit fusion. The pattern of susceptibility to cholesterol-labeled oligonucleotides among HIV-1 strains was the same as reported for nonmembrane-associating polyanions such as dextran sulfate, but the cholesterol-labeled oligonucleotides were effective at lower concentrations. Substitution of a basic 33 amino acid V3 loop sequence from the envelope protein of a resistant strain into a susceptible strain made the envelope protein resistant to inhibition. Inhibition by cholesterol-labeled oligonucleotides was abrogated by the polycation DEAE-dextran. Cholesterol-labeled oligonucleotides bound to nonraft regions of the plasma membrane and did not inhibit HIV virus binding to cells. Many infectious agents first associate with target cells via relatively nonspecific charge interactions; our data suggest that molecules that combine a membrane-targeting motif with multiple negative charges might be useful to modify these interactions. |
| Inhibition of chemokine receptor function by membrane cholesterol oxidation Nguyen, D. H. and D. D. Taub (2003), Exp Cell Res 291(1): 36-45. Abstract: Membrane cholesterol is required to maintain chemokine receptor conformation and function for CXCR4 and CCR5. We previously demonstrated that chemokines preferentially bind to receptors within lipid rafts, which are cholesterol- and sphingolipid-rich membrane microdomains. To further elucidate the role of cholesterol in chemokine receptor function, we examined the effects of membrane cholesterol oxidation by cholesterol oxidase (CO), which enzymatically converts cholesterol to 4-cholesten-3-one. Here, we demonstrate that CO treatment (0.25-2.0 U/ml) of human T cells inhibits CXCL12 (SDF-1alpha) and CCL4 (MIP-1beta) binding to cell surface CXCR4 and CCR5, respectively, resulting in the inhibition of chemokine-mediated intracellular calcium mobilization and chemotaxis. The effects were significantly enhanced by cotreatment with low-dose sphingomyelinase (SMase) (0.125 mU/ml), which produced little inhibitory effect by itself. CO and SMase treatment also inhibited HIV-1 infection through CXCR4, but not virus replication. Similar to the removal of membrane cholesterol, CO/SMase treatment induced conformation changes in the chemokine receptors as detected by differential loss in binding of epitope-specific monoclonal antibodies. We conclude that the native form of cholesterol with the hydroxyl group at C3 is critical to CXCR4 and CCR5 conformation and function. |
| Inhibition of cholesterol absorption and synthesis in rats by sesamin Hirose, N., T. Inoue, et al. (1991), J Lipid Res 32(4): 629-38. Abstract: The effects of sesamin, a lignan from sesame oil, on various aspects of cholesterol metabolism were examined in rats maintained on various dietary regimens. When given at a dietary level of 0.5% for 4 weeks, sesamin reduced the concentration of serum and liver cholesterol significantly irrespective of the presence or absence of cholesterol in the diet, except for one experiment in which the purified diet free of cholesterol was given. On feeding sesamin, there was a decrease in lymphatic absorption of cholesterol accompanying an increase in fecal excretion of neutral, but not acidic, steroids, particularly when the cholesterol-enriched diet was given. Sesamin inhibited micellar solubility of cholesterol, but not bile acids, whereas it neither bound taurocholate nor affected the absorption of fatty acids. Only a marginal proportion (ca. 0.15%) of sesamin administered intragastrically was recovered in the lymph. There was a significant reduction in the activity of liver microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase after feeding sesamin, although the activity of hepatic cholesterol 7 alpha-hydroxylase, drug metabolizing enzymes, and alcohol dehydrogenase remained uninfluenced. Although the weight and phospholipid concentration of the liver increased unequivocally on feeding sesamin, the histological examination by microscopy showed no abnormality, and the activity of serum GOT and GPT remained unchanged. Since sesamin lowered both serum and liver cholesterol levels by inhibiting absorption and synthesis of cholesterol simultaneously, it deserves further study as a possible hypocholesterolemic agent of natural origin. |
| Inhibition of cholesterol absorption associated with a PPAR alpha-dependent increase in ABC binding cassette transporter A1 in mice Knight, B. L., D. D. Patel, et al. (2003), J Lipid Res 44(11): 2049-58. Abstract: Dietary supplementation with the peroxisome proliferator-activated receptor alpha (PPAR alpha) ligand WY 14,643 gave rise to a 4- to 5-fold increase in the expression of mRNA for the ATP binding cassette transporter A1 (ABCA1) in the intestine of normal mice. There was no effect in the intestine of PPAR alpha-null mice. Consumption of a high-cholesterol diet also increased intestinal ABCA1 expression. The effects of WY 14,643 and the high-cholesterol diet were not additive. WY 14,643 feeding reduced intestinal absorption of cholesterol in the normal mice, irrespective of the dietary cholesterol concentration, and this resulted in lower diet-derived cholesterol and cholesteryl ester concentrations in plasma and liver. At each concentration of dietary cholesterol, there was a similar significant inverse correlation between intestinal ABCA1 mRNA content and the amount of cholesterol absorbed. The fibrate-induced changes in the intestines of the normal mice were accompanied by an increased concentration of the mRNA encoding the sterol-regulatory element binding protein-1c gene (SREBP-1c), a known target gene for the oxysterol receptor liver X receptor alpha (LXR alpha). There was a correlation between intestinal ABCA1 mRNA and SREBP-1c mRNA contents, but not between SREBP-1c mRNA content and cholesterol absorption. These results suggest that PPAR alpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXR alpha. |
| Inhibition of cholesterol absorption by alpha-olefin maleic acid Miettinen, T. A. (2001), Dig Liver Dis 33(2): 121-2. |
| Inhibition of cholesterol absorption by HMG-CoA reductase inhibitor Miettinen, T. A. (1991), Eur J Clin Pharmacol 40 Suppl 1: S19-21. Abstract: In subjects with familial hypercholesterolemia cholesterol absorption efficiency was insignificantly reduced during a short-term more consistently during long-term pravastatin treatment. A cholesterol feeding had no effect on LDL cholesterol level but reduced absorption efficiency during a long-term lovastatin treatment. |
| Inhibition of cholesterol absorption by neomycin, benzodiazepine derivatives and ketoconazole Kesaniemi, Y. A. and T. A. Miettinen (1991), Eur J Clin Pharmacol 40 Suppl 1: S65-7. Abstract: Neomycin and a benzodiazepine derivative (RO16-0521) inhibit similarly cholesterol absorption in man but the serum cholesterol level is reduced only by neomycin. Reason(s) for the difference are unknown. Ketoconazole inhibits 14 alpha-demethylation of lanosterol so that cholesterol synthesis is reduced. The agent inhibits also cholesterol absorption. The serum cholesterol level is reduced by about 20%, the lowering being potentiated by a simultaneous cholestyramine treatment. |
| Inhibition of cholesterol absorption by phytosterol-replete wheat germ compared with phytosterol-depleted wheat germ Ostlund, R. E., Jr., S. B. Racette, et al. (2003), Am J Clin Nutr 77(6): 1385-9. Abstract: BACKGROUND: Low-fat vegetable foods contain phytosterols, but it is not known whether they are in biologically active forms or whether their concentrations are high enough to reduce cholesterol absorption and favorably affect lipid metabolism. OBJECTIVE: The objective was to establish whether the selective removal of phytosterols from wheat germ would increase the cholesterol absorption measured from test meals composed of wheat germ muffins. DESIGN: Wheat germ, which has a high content of phytosterols relative to total fat, was chosen as a low-fat test food. Cholesterol absorption was measured 3 times in 10 subjects. Each test meal was a muffin containing 30 mg heptadeuterated cholesterol tracer and, in random order, 80 g original wheat germ containing 328 mg phytosterols, wheat germ from which phytosterols had been selectively extracted, or extracted wheat germ reconstituted with purified phytosterols. Changes in cholesterol absorption were monitored by the measurement of tracer enrichment of plasma cholesterol 4 and 5 d after each meal with the use of negative ion mass spectrometry. RESULTS: Tracer enrichment of plasma cholesterol was 42.8% higher after consumption of phytosterol-free wheat germ than after that of the original wheat germ (0.415 +/- 0.035 compared with 0.291 +/- 0.024 micro mol tracer/mmol cholesterol; P < 0.01). Tracer enrichment of plasma cholesterol was not significantly different between the wheat germ with extracted-and-reconstituted phytosterol (0.305 +/- 0.022 micro mol tracer/mmol cholesterol) and the original wheat germ. CONCLUSION: The efficiency of cholesterol absorption from test meals was substantially lower after consumption of original wheat germ than after consumption of phytosterol-free wheat germ, which suggests that endogenous phytosterols in wheat germ and possibly in other low-fat vegetable foods may have important effects on cholesterol absorption and metabolism that are independent of major nutrients. |
| Inhibition of cholesterol absorption by plant sterols for mass intervention Ikeda, I. and M. Sugano (1998), Curr Opin Lipidol 9(6): 527-31. Abstract: Plant sterols and stanols lower serum cholesterol by inhibiting intestinal absorption of cholesterol. Because of their safety and efficacy, their application for mass intervention is promising. The use of fatty acid esters of stanols is particularly helpful because stanols readily mix with dietary fats in this form and their hypocholesterolemic efficacy is greater than in the free form. |
| Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte Repa, J. J., J. M. Dietschy, et al. (2002), J Lipid Res 43(11): 1864-74. Abstract: Intestinal cholesterol absorption is a major determinant of plasma low density lipoprotein-cholesterol (LDL-C) concentrations. Ezetimibe (SCH 58235) and its analogs SCH 48461 and SCH 58053 are novel potent inhibitors of cholesterol absorption whose mechanism of action is unknown. These studies investigated the effect of SCH 58053 on cholesterol metabolism in female 129/Sv mice. In mice fed a low cholesterol rodent diet containing SCH 58053, cholesterol absorption was reduced by 46% and fecal neutral sterol excretion was increased 67%, but biliary lipid composition and bile acid synthesis, pool size, and pool composition were unchanged. When the dietary cholesterol content was increased either 10- or 50-fold, those animals given SCH 58053 manifested lower hepatic and biliary cholesterol concentrations than did their untreated controls. Cholesterol feeding increased the relative mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1), ABC transporter G5 (ABCG5), and ABC transporter G8 (ABCG8) in the jejunum, and of ABCG5 and ABCG8 in the liver, but the magnitude of this increase was generally less if the mice were given SCH 58053. We conclude that the inhibition of cholesterol absorption effected by this new class of agents is not mediated via changes in either the size or composition of the intestinal bile acid pool, or the level of mRNA expression of proteins that facilitate cholesterol efflux from the enterocyte, but rather may involve disruption of the uptake of luminal sterol across the microvillus membrane. |
| Inhibition of cholesterol absorption with CP-148,623 lowers serum cholesterol in humans Harris, W. S., S. L. Windsor, et al. (1997), Clin Pharmacol Ther 61(3): 385-9. Abstract: OBJECTIVE: To determine the effects of the reduction of intestinal cholesterol absorption with CP-148,623 on serum cholesterol levels in men with mild hyperlipidemia. METHODS: In an outpatient study in a university medical center, healthy male volunteers (n = 25) with borderline-high serum cholesterol levels participated in a double-blind, placebo-controlled parallel-group study. A 3-week dietary run-in period was followed by 2 weeks of treatment with either CP-148,623 (300 mg twice a day; n = 12) or placebo (n = 13). RESULTS: Fractional cholesterol absorption (by the dual-isotope, continuous-feeding technique), fecal neutral sterol excretion, and serum lipids were measured after the diet run-in and after the treatment periods. CP-148,623 caused a marked inhibition (by 38%) of fractional cholesterol absorption (50% +/- 2% baseline to 31% +/- 1%) and a 71% increase in fecal neutral sterol excretion (481 +/- 39 mg/day baseline to 804 +/- 55 mg/day), compared with negligible changes in the placebo group (p < 0.0001 for both). Mean percent reductions from baseline in serum low-density lipoprotein (LDL) cholesterol levels were 11.6% with CP-148,623 (119 +/- 17 mg/dl to 104 +/- 13 mg/dl) versus a nonsignificant 1.8% reduction with placebo (change with CP-148,623 versus placebo, p < 0.0002). CONCLUSIONS: In healthy male volunteers with mild hypercholesterolemia, treatment for 2 weeks with 600 mg/day CP-148,623 inhibited fractional cholesterol absorption by 35% to 40%, increased fecal neutral sterol excretion by 60% to 70%, and reduced serum LDL cholesterol by 10% to 12%. |