| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effect of tamoxifen on cholesterol synthesis in HepG2 cells and cultured rat hepatocytes Holleran, A. L., B. Lindenthal, et al. (1998), Metabolism 47(12): 1504-13. Abstract: The objective of this study was to investigate the mechanisms by which tamoxifen modifies cholesterol metabolism in cellular models of liver metabolism, HepG2 cells and rat hepatocytes. The effect of tamoxifen on cholesterol and triglyceride-palmitate synthesis was measured using isotopomer spectral analysis (ISA) and gas chromatography-mass spectrometry (GC-MS) and compared with the effects of progesterone, estradiol, the antiestrogen ICI 182,780, and an oxysterol, 25-hydroxycholesterol (25OHC). Cholesterol synthesis in cells incubated in the presence of either 1-(13)Cacetate, U-13Cglucose, or 4,5-(13)Cmevalonate for 48 hours was reduced in the presence of 10 micromol/L tamoxifen and 12.4 micromol/L 25OHC in both HepG2 cells and rat hepatocytes. The ISA methodology allowed a clear distinction between effects on synthesis and effects on precursor enrichment, and indicated that these compounds did not affect enrichment of the precursors of squalene. Progesterone was effective in both cell types at 30 micromol/L and only in HepG2 cells at 10 micromol/L. Estradiol and ICI 182,780 at 10 micromol/L did not inhibit cholesterol synthesis. None of the compounds altered the synthesis of triglyceride-palmitate in either cell type. Treatment of cells with tamoxifen produced accumulation of three sterol precursors of cholesterol, zymosterol, desmosterol, and delta8 cholesterol. This pattern of precursors indicates inhibition of delta24,25 reduction in addition to the previously described inhibition of delta8 isomerase. We conclude that tamoxifen is an effective inhibitor of the conversion of lanosterol to cholesterol in cellular models at concentrations comparable to those present in the plasma of tamoxifen-treated individuals. Our findings indicate that this mechanism may contribute to the effect of tamoxifen in reducing plasma cholesterol in humans. |
| Effect of tamoxifen on serum cholesterol and lipoproteins during chemohormonal therapy Dnistrian, A. M., M. K. Schwartz, et al. (1993), Clin Chim Acta 223(1-2): 43-52. Abstract: The effect of tamoxifen on serum cholesterol, high density lipoprotein cholesterol (HDL-cholesterol), low density lipoprotein cholesterol (LDL-cholesterol) and the ratio of LDL-cholesterol to HDL-cholesterol (LDL-C/HDL-C) was investigated in breast cancer patients undergoing therapy for advanced disease. Longitudinal studies in 24 patients treated with tamoxifen (10 mg, twice daily) indicated average decreases in total serum cholesterol (17%) and LDL-cholesterol (27%), whereas the effect of tamoxifen on HDL-cholesterol varied with the individual patient. There was a significant decrease in the LDL-C/HDL-C ratio (33%) consistent with a decreased risk for coronary artery disease. This beneficial influence of tamoxifen on risk factors associated with cardiovascular disease was evident in both premenopausal and postmenopausal patients whether tamoxifen was administered alone or in combination with cytotoxic chemotherapy. |
| Effect of taurine on cholesterol degradation and bile acid pool in rats fed a high-cholesterol diet Chen, W., N. Nishimura, et al. (2003), Adv Exp Med Biol 526: 261-7. |
| Effect of taurine on cholesterol metabolism in hamsters: up-regulation of low density lipoprotein (LDL) receptor by taurine Murakami, S., Y. Kondo, et al. (2002), Life Sci 70(20): 2355-66. Abstract: The effects of taurine on hepatic cholesterol metabolism were investigated in hamsters fed a high-fat diet or normal chow. Two weeks-treatment of taurine at 1% in drinking water prevented high-fat diet-induced increase in cholesterol levels of serum and liver. The decrease in serum cholesterol by taurine was due to decrease in non-HDL cholesterols. A similar tendency was noted in serum and liver cholesterol levels of hamsters fed a normal diet. In hamsters fed a high-fat diet, taurine prevented elevation in hepatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and increased the activity of cholesterol 7alpha-hydroxylase. Taurine also increased cholesterol 7alpha-hydroxylase activity in hamsters fed normal chow. Studies on liver membranes revealed that taurine increased 125I-labeled LDL binding by 52% and 58% in hamsters fed either a normal chow or high-fat diet, respectively. Furthermore, LDL kinetic analysis showed that taurine intake resulted in significant faster plasma LDL fractional catabolic rates (FCR). These results suggest that taurine elevates hepatic LDL receptor and thereby decreases serum cholesterol levels, an event which may be the result of hepatic cholesterol depletion as a consequence of increased bile acid synthesis via enhancement of cholesterol 7alpha-hydroxylase activity. Thus, up-regulation of the LDL receptor and subsequent increase in receptor- mediated LDL turnover may be a key event in the cholesterol-lowering effects of taurine in hamsters. |
| Effect of testosterone on atherogenesis in cholesterol-fed rabbits with similar plasma cholesterol levels Larsen, B. A., B. G. Nordestgaard, et al. (1993), Atherosclerosis 99(1): 79-86. Abstract: The aim was to examine the effect of testosterone on atherogenesis in cholesterol-fed, castrated male rabbits not mediated via different plasma cholesterol levels. The rabbits in the testosterone group (n = 19) and in the placebo group (n = 17) were injected intramuscularly twice weekly for 17 weeks with 25 mg testosterone enantate and placebo, respectively, reaching plasma testosterone levels of 50-150 nmol/l in the testosterone group. No effect of testosterone on liver function or body weight was detected, but at week 15 mean blood pressure was 75 +/- 2 mmHg (mean +/- S.E.) in the testosterone group compared with 69 +/- 2 mmHg in the placebo group (P < 0.05). To reduce variation in plasma cholesterol between the two groups, the amount of cholesterol fed to each rabbit was adjusted on the basis of weekly determinations of plasma cholesterol; the mean plasma cholesterol levels during the 17 weeks were 20.9 +/- 1.0 and 20.4 +/- 0.9 mmol/l for the placebo and testosterone groups. In the intima-inner medias of the aortic arch, the thoracic and the abdominal aorta there were no consistent significant differences in aortic cholesterol content, expressed either as nmol/cm2 or nmol/mg protein, between the two groups. However, the aortic cholesterol content tended to be lower in the testosterone group than in the placebo group. These findings suggest that in cholesterol-fed, castrated male rabbits, testosterone does not promote atherogenesis by an effect directly on the arterial wall. |
| Effect of the ACAT inhibitor CI-976 on plasma cholesterol concentrations and distribution in hamsters fed zero- and low-cholesterol diets Krause, B. R., R. F. Bousley, et al. (1992), Clin Biochem 25(5): 371-7. Abstract: The overall objective of the present study was to determine if the ACAT inhibitor CI-976 can lower plasma cholesterol in hamsters fed zero or low, "human-like" levels of cholesterol. With a purified diet containing zero dietary cholesterol, CI-976 significantly lowered VLDL cholesterol (VLDL-C), but not total plasma cholesterol (TPC). When 0.06% cholesterol was added to this diet, reductions in both VLDL and LDL cholesterol (LDL-C) lowered TPC. Efficacy was still greater with 0.2% dietary cholesterol, but not potency. Mixing CI-976 into the purified diet resulted in greater decreases in VLDL-C compared to gavage administration, but LDL-C reductions with 0.2% cholesterol were optimal with gavage. With nonpurified, chow-based diets efficacy was markedly greater with diet-admix administration, regardless of the amount of dietary cholesterol. CI-976 inhibited cholesterol absorption with chow-based diets more potently compared to nonabsorbable agents (e.g., beta-sitosterol, tigogenin cellobioside), and the lowering of LDL-C was greatest when inhibition of cholesterol absorption was maximal. We conclude that the ACAT inhibitor CI-976 is efficacious in hamster models which utilize human-like levels of dietary cholesterol. Moreover, the data suggest that the pharmacologic responses to lipophilic ACAT inhibitors in the hamster, or even other lipid-regulating drugs, are likely to depend not only on the type of basal diet but also on the mode of drug administration. |
| Effect of the ACAT inhibitor, HL-004, on cholesterol metabolism in macrophages Murakami, S., I. Yamagishi, et al. (1996), Cell Mol Biol (Noisy-le-grand) 42(6): 865-72. Abstract: The effects of a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, HL-004, on cholesterol metabolism were examined in mice peritoneal macrophages. Cholesteryl ester-rich foam cells were induced by incubating macrophages with acetylated LDL. HL-004 prevented the accumulation of cholesteryl ester in the presence of the cholesterol acceptor, HDL. In the absence of HDL, HL-004 generated large amounts of free cholesterol in the cell. Moreover, HL-004 stimulated the efflux of cholesterol from preestablished foam cells in the presence of HDL. These results suggest that the inhibition of foam cell formation and the stimulation of foam cell regression by HL-004 are attributed to intracellular ACAT inhibition, and that HL-004 would be expected to exhibit an antiatherosclerotic effect through direct action on arterial wall. |
| Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans Hainer, J. W., J. G. Terry, et al. (1994), Clin Pharmacol Ther 56(1): 65-74. Abstract: Intestinal cholesterol esterification by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) is a presumed prerequisite for cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT inhibitor (DuP 128: N'-(2,4-difluorophenyl)-N-5-(4,5-diphenyl-1H-imidazol-2-ylthio)pe ntyl- N-heptylurea) on cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day; six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% +/- 11.4% reduction in cholesterol absorption (p < 0.05 versus placebo): 17.6% +/- 8.4% at 900 mg, 9.1% +/- 11.4% at 1800 mg, and 17.1% +/- 12.9% at 3600 mg. Neomycin induced a 26.4% +/- 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein cholesterol by 22.4% +/- 9.2% and 24.0% +/- 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% +/- 11% (difference not significant) and 4.95% +/- 14.3% (p = 0.05). ACAT inhibitors limit cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small. |
| Effect of the apolipoprotein A-I and surface lipid composition of reconstituted discoidal HDL on cholesterol efflux from cultured fibroblasts Zhao, Y., D. L. Sparks, et al. (1996), Biochemistry 35(51): 16510-8. Abstract: Five series of reconstituted discoidal HDL (LpA-I) particles have been prepared, and their constituents, apolipoprotein A-I (apoA-I), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), unesterified cholesterol (UC), phosphatidylinositol (PI), or sphingomyelin (SM), have been systematically varied to elucidate the relationship between HDL composition and cholesterol efflux from non-cholesterol-loaded human skin fibroblasts. The physical properties, such as hydrodynamic diameters, alpha-helix contents, and surface potentials, of these LpA-I have been measured and related to the ability of the LpA-I to accept cellular cholesterol. The results show that for LpA-I particles containing 2, 3, or 4 apoA-I per particle, Lp4A-I are the best acceptors of cellular cholesterol, followed by Lp3A-I and then Lp2A-I particles. Discoidal Lp2A-I with variations in POPC content, from 121 to 266 mol/particle; show no difference in their abilities to promote cholesterol efflux. Similarly, inclusion of 7 and 15 mol of free cholesterol to Lp2A-I also does not affect their ability to accept cellular cholesterol. However, increasing the content of either PI or SM, up to 20 mol/particle, is associated with significantly increased abilities of the LpA-I to promote cholesterol efflux. The efflux of cellular cholesterol to discoidal LpA-I particles is independent of specific changes in apoA-I conformation and charge, but appears to be positively related to major changes in the size of the lipoprotein particle. The study suggests that in contrast to interlipoprotein cholesterol transfers, the efflux of cholesterol from cultured fibroblasts is less sensitive to factors that affect the frequency of molecular collisions and more dependent on the ability of an HDL particle to absorb and retain cholesterol molecules. Since SM and PI appear to modulate this adsorption/desorption of cholesterol to HDL, variations in the concentration of these lipids within HDL would be expected to affect plasma cholesterol homeostasis. |
| Effect of the cholesterol and protein diet on cytochrome P-450 dependent monooxygenase activity Plewka, A. and M. Kaminski (1995), Med Pr 46(1): 17-23. Abstract: The effect of cholesterol and protein diet on mixed-function oxidase activity and desaturation of fatty acids were studid as well as phenobarbital inducibility of those parameters. Investigations were carried out on Wistar adult male rats. The animals were on the cholesterol (0.25%) and protein (32%) diet for 45 days. Cytochrome P-450 and cytochrome b5 contents, NADPH-cytochrome P-450 reductase, NADH-cytochrome b5 reductase, aniline hydroxylase and 4-aminopyrine N-demethylase activities were measured in a hepatic microsomal fraction. The cholesterol diet exerted a negative effect on all parameters except NADH-cytohrom b5 reductase. The protein diet did not change the activity or levels of enzymes under study. The only exception applied to induction of NADH-cytochrome b5 reductase and 4-aminopyrine N-demethylase activities. Simultaneous treatment with phenobarbital had a heterogenous effect depending on the type of diet and parameters examined. |
| Effect of the cholesterol content of a formula on the lipid compositions of plasma lipoproteins and red blood cell membranes in early infancy Katoku, Y., M. Yamada, et al. (1996), Am J Clin Nutr 64(6): 871-7. Abstract: We investigated whether or not a regular formula for full-term infants supplemented with cholesterol (cholesterol-fortified) would increase the plasma cholesterol concentration and alter the red blood cell (RBC) membrane lipid composition in healthy full-term infants compared with their breast-fed counterparts. At 1 mo of age, total plasma cholesterol and low-density-lipoprotein (LDL) cholesterol were significantly higher in the breast-fed infants than in the cholesterol-unfortified, formula-fed infants. At 3 mo of age, total cholesterol and LDL cholesterol were significantly higher in the breast-fed infants than in the two formula-fed infant groups. These significant differences had disappeared by 6 mo of age. Although the cholesterol-unfortified, formula-fed infants had lower proportions of docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) in the RBC membranes compared with the breast-fed group at 6 mo, DHA and EPA concentrations in the cholesterol-fortified, formula-fed infants were not significantly different. The results of the present study suggest that the plasma cholesterol concentration and fatty acid pattern of the RBC membranes in infants fed a cholesterol-fortified formula may be much closer to those in breast-fed infants than in infants fed a cholesterol-unfortified formula. |
| Effect of the cholesterol content of reconstituted LpA-I on lecithin:cholesterol acyltransferase activity Sparks, D. L., G. M. Anantharamaiah, et al. (1995), J Biol Chem 270(10): 5151-7. Abstract: The production of cholesteryl ester (CE) by lecithin: cholesterol acyl transferase (LCAT) is elevated significantly in hyperlipidemic subjects at high risk for coronary artery disease. To elucidate the molecular events involved, the relationship between LCAT activation and apolipoprotein (apo) A-I charge and structure in high density lipoproteins (HDL) has been studied in both native HDL and homogeneous recombinant HDL (Lp2A-I) particles containing apoA-I, palmitoyloleoyl phosphatidylcholine and cholesterol. Increasing the cholesterol content of discoidal Lp2A-I from 4 to 26 molecules/particle raises the maximum rate of cholesterol esterification by LCAT (Vmax) from 3.1 to 9.2 nmol CE/h/unit of LCAT and increases the apparent Km from 0.5 to 3.5 microM cholesterol. Similarly, increasing the cholesterol content in triolein core-containing Lp2A-I (4-18 molecules/particle) and in native HDL3 (12-21 molecules/particle) also significantly increases the Vmax for LCAT (2.8-7.7 and 0.5-3.6 nmol CE/h, respectively) and raises the Km values (7.6-36.9 and 7.3-8.5 microM cholesterol, respectively). In contrast, changes in the cholesterol content of native and recombinant HDL have no significant effect on the apparent Km values when expressed in terms of the concentration of either apoA-I or palmitoyloleoyl phosphatidylcholine. This appears to indicate that interfacial cholesterol content has no effect on the binding affinity of LCAT to different LpA-I particles but directly affects catalysis by modulating the interaction of cholesterol molecules with the active site of LCAT. Increasing the cholesterol content of the different HDL particles progressively increases the particle net negative charge, and these changes in apoA-I charge are strongly correlated with both the Vmax and apparent Km values for LCAT. This suggests that the conformation and charge of apoA-I play a central role in LCAT activation and that these parameters are influenced by the amount of cholesterol in the surface of HDL particles. |
| Effect of the hypocholesterolemic agent YM-16638 on cholesterol biosynthesis activity and apolipoprotein B secretion in HepG2 and monkey liver Goto, S. and T. Shimokawa (1999), Jpn J Pharmacol 79(1): 75-82. Abstract: YM-16638 (5-3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio-1,3,4-++ +thiadiazol-2-yl thio acetic acid) showed a strong hypocholesterolemic effect in humans and monkeys. To clarify the mechanism of this hypocholesterolemic effect, the action of YM-16638 on cholesterol biosynthesis in the cultured human hepatoma cell line HepG2 and cynomolgus monkey liver was examined. Cholesterol biosynthesis activity derived from 14Cacetic acid, 3H/14Cmevalonic acid or 14Cisopentenyl pyrophosphate substrates was significantly decreased, but not that from 3Hfarnesyl pyrophosphate or 3Hsqualene substrates in HepG2 cells treated with YM-16638. Simultaneously, treatment of these cells with YM-16638 changed neither the rate of apolipoprotein B synthesis from 35Smethionine nor its secretion. In addition, the activities of hepatic cholesterol biosynthesis enzymes HMG-CoA reductase, mevalonate kinase (MK), isopentenyl pyrophosphate isomerase (IPPI), farnesyl pyrophosphate synthase (FPPS), squalene synthase and squalene epoxidase were measured in monkeys fed a diet supplemented with YM-16638. Among these enzymes, MK, IPPI and FPPS activities in the YM-16638-treated group significantly decreased by 38%, 56% and 30%, respectively, when compared to those from control animals receiving no drug treatment. These results indicate that YM-16638 has the characteristics of a cholesterol biosynthesis inhibitor. |
| Effect of the LDL-/HDL-cholesterol quotient on progression and regression of arteriosclerotic lesions. An analysis of controlled angiographic intervention studies Gohlke, H. (1992), Wien Klin Wochenschr 104(11): 309-13. Abstract: The importance of hypercholesterolemia for the development of atherosclerotic lesions is undebatable. It is less evident, however, whether the progression of established lesions can be influenced by modifying lipid levels. The review of seven controlled angiographic intervention trials shows that different criteria are used to define progression of lesions. The relation of progression to regression (progression/regression ratio), however, is a useful marker for the activity of coronary artery disease. Patients with familial hypercholesterolemia have a progression/regression ratio of between 3 and 7. There is a consistent relationship between the progression/regression ratio and the LDL-/HDL-cholesterol ratio in both control and intervention groups in these trials. Groups with a LDL-/HDL-cholesterol ratio of 5 have six times more progression than regression. If the LDL-/HDL-cholesterol ratio is less than 2.5 regression occurs more often than progression (i.e. progression/regression ratio less than 1). Thus, in the management of hyperlipidemic patients a LDL-/HDL-cholesterol ratio of less than 2.5 should be achieved if regression of atherosclerotic lesions is desired. |
| Effect of the monooxygenase activity inhibitor ketoconazole on cholesterol esterification in mouse peritoneal macrophages Dushkin, M. I., E. V. Mandrikova, et al. (1990), Biokhimiia 55(9): 1607-15. Abstract: In order to determine the feasible role of monooxygenases in regulation of the macrophage acyl-CoA: cholesterol acyltransferase (ACAT) activity, the effects of ketoconazole on the activities of benz(a)pyrene hydroxylase and ACAT as well as on the 14Coleate incorporation into cholesterol esters in cultured mouse peritoneal macrophages (MPM) were studied. Ketoconazole (0.5-50 M) inhibited the benz(a)pyrene hydroxylase activity but increased the free cholesterol (FC) level in MPM cultured with an acetylated low density lipoprotein (acetyl-LDL). An addition of ketoconazole (1-50 M) eliminated the increase in the rate of FC esterification after incubation of MPM with acetyl-LDL (but not with 25-hydroxycholesterol). In contrast, progesterone, an ACAT activity inhibitor, used at 5-30 M diminished the rate of FC esterification, when MPM were incubated with acetyl-LDL of 25-hydroxycholesterol. Ketoconazole provoked a dose-dependent decrease of the 3HFC incorporation into macrophage polar oxysteroids. The data obtained suggest that the ketoconazole (1-30 M) effect on FC esterification in MPM cultured with acetyl-LDL is determined by its inhibiting monooxygenases, which produce oxidized forms of FC that are potential activators of ACAT. |
| Effect of the new HMG-CoA reductase inhibitor cerivastatin (BAY W 6228)on migration, proliferation and cholesterol synthesis in arterial myocytes Corsini, A., L. Arnaboldi, et al. (1996), Pharmacol Res 33(1): 55-61. Abstract: The major relation existing between cell growth, migration and cholesterol homeostasis prompted us to investigate the effect of the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin (BAY W 6228) on these cellular events. The molecule inhibited in a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of 3H-thymidine) of rat arterial SMC with IC50 values of 2.7 microM and 0.5 microM, respectively. Among the tested statins BAY W 6228 resulted to be the most potent inhibitor of cholesterol synthesis and cell proliferation. Conditions producing 80-90% inhibition of cholesterol synthesis correlate with approximately 50% inhibition of cell growth. Similar results were obtained in SMC from human femoral artery. The in vitro inhibition of cell migration and proliferation induced by BAY W 6228 (80% decrease) was completely prevented by the addition of mevalonate and partially prevented (60-80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites-probably through a prenylated protein(s)-in regulating these cellular events. The present results provide evidence that BAY W 6228 interferes, at least in vivo, with smooth muscle cells migration and proliferation, major processes involved in atherogenesis. |
| Effect of the nonenzymatic glycosylation of high density lipoprotein-3 on the cholesterol ester transfer protein activity Lemkadem, B., D. Loiseau, et al. (1999), Lipids 34(12): 1281-6. Abstract: This study examines the relationship between high density lipoprotein-3 (HDL-3) glycation and cholesteryl ester transfer mediated by cholesteryl ester transfer protein (CETP). HDL-3 were glycated with various glucose concentrations (0-200 mM) for 3 d at 37 degrees C with sodium cyanoborohydride as reducing agent and antioxidants. About 47% of the lysine residues were glycated in the presence of 200 mM glucose, resulting in an increase in the cholesterol ester (CE) transfer of about 30%. Apparent kinetic parameters expressed as maximal transfer (appT(max)) and CE concentration at half of T(max)(appK(H)) of CETP activity with glycated HDL-3 showed conflicting and paradoxical data: an increase in CETP activity associated with a decrease of CETP affinity. These alterations were not due to a change in HDL-3 lipid and protein composition nor to a peroxidative process but were associated with an increase in HDL-3 electronegativity and a decrease of HDL-3 fluidity. This study suggests that glycation modifies the apolipoprotein's conformation and solvation which are major determinants of interfacial properties of HDL-3. These modifications in turn affect CETP reactivity. |
| Effect of the plant compound indole-3-carbinol on hepatic cholesterol homoeostasis LeBlanc, G. A., J. D. Stuart, et al. (1994), Food Chem Toxicol 32(7): 633-9. Abstract: The aim of this study was to elucidate the effects of the compound indole-3-carbinol (I3C), which is found in cruciferous vegetables, on hepatic cholesterol homoeostasis and metabolism in male CD-1 mice. Oral administration of 500 and 750 mg I3C/kg/day to mice for 1 wk resulted in increased liver mass and microsomal protein content. Hepatic microsomal cholesterol levels were not significantly altered following treatment with 100 and 250 mg I3C/kg/day, but were significantly decreased following treatment with 500 and 750 mg/kg/day. Conversely, the lower doses of I3C administered decreased serum cholesterol levels whereas the higher doses of I3C had no effect on this parameter. Alterations in cholesterol homoeostasis by I3C were not related to liver hypertrophy, since administration of phenobarbital to mice increased liver size, but had no significant effect on hepatic microsomal or serum cholesterol levels. Activities of the hepatic enzymes cholesterol ester hydrolase and cholesterol 7 alpha-hydroxylase were not altered by I3C. However, 500 and 750 mg I3C/kg/day elevated the activity of hepatic acyl-CoA:cholesterol acyltransferase (ACAT), the enzyme responsible for the formation of hepatic cholesteryl esters. These results demonstrate that (a) I3C lowers serum cholesterol levels at concentrations that have no discernible effect on hepatic cholesterol homoeostasis, and (b) at higher doses of I3C, hepatic microsomal cholesterol levels are significantly lowered and ACAT activity is significantly elevated. These latter effects are not accompanied by changes in serum cholesterol levels and may represent compensatory mechanisms to restore cholesterol homoeostasis in the body. Mechanisms responsible for the effects of I3C on cholesterol homoeostasis are proposed. |
| Effect of the prokinetic agent, erythromycin, in the Richardson ground squirrel model of cholesterol gallstone disease Xu, Q. W., R. B. Scott, et al. (1998), Hepatology 28(3): 613-9. Abstract: Impaired gallbladder motility and delayed intestinal transit contribute to cholesterol gallstone formation by impeding the enterohepatic circulation of bile salts and causing gallbladder stasis. The therapeutic value of erythromycin, a prokinetic motilin analog, was evaluated in an animal model of gallstone formation. Eighty ground squirrels were fed either a trace- (control) or a high- (1%) cholesterol diet. Half of each diet group received either erythromycin stearate or placebo orally twice daily for 4 weeks. Biliary lipid secretion and bile salt pool size were determined via common duct cannulation. Gallbladder contractile response to cholecystokinin (CCK) was studied in vitro. Intestinal transit was evaluated in vivo by 51Cr marker. In the placebo-treated group, fed the high- versus the trace-cholesterol diet, bile salt secretion decreased (trace-cholesterol + placebo, 21.0 +/- 1.8 nmol/min/g liver vs. high-cholesterol + placebo, 9.3 +/- 1.4 nmol/min/g liver), cholesterol saturation index (CSI) doubled (trace-cholesterol + placebo, 0.61 +/- 0.06 vs. high-cholesterol + placebo, 1.30 +/- 0.04), nucleation time shortened (trace-cholesterol + placebo, > 21 days vs. high-cholesterol + placebo, 6.4 +/- 1.0 days), cholesterol crystals formed, gallbladder contractility diminished, and intestinal transit was delayed (each P <.05). Erythromycin treatment of animals on the high-cholesterol diet restored gallbladder contractility and intestinal transit to control levels, increased bile salt secretion, reduced the total bile salt pool, lowered the cholesterol saturation of bile, lengthened the nucleation time, and so reduced crystal formation (each P <.05). Erythromycin enhances gallbladder motility and hastens intestinal transit, promoting more rapid enterohepatic cycling of bile salts. This increases bile salt secretion, improves cholesterol solubility, and reduces crystal development. |
| Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide Xu, X., R. Bittman, et al. (2001), J Biol Chem 276(36): 33540-6. Abstract: Ordered lipid domains enriched in sphingolipids and cholesterol (lipid rafts) have been implicated in numerous functions in biological membranes. We recently found that lipid domain/raft formation is dependent on the sterol component having a structure that allows tight packing with lipids having saturated acyl chains (Xu, X., and London, E. (2000) Biochemistry 39, 844-849). In this study, the domain-promoting activities of various natural sterols were compared with that of cholesterol using both fluorescence quenching and detergent insolubility methods. Using model membranes, it was shown that, like cholesterol, both plant and fungal sterols promote the formation of tightly packed, ordered lipid domains by lipids with saturated acyl chains. Surprisingly ergosterol, a fungal sterol, and 7-dehydrocholesterol, a sterol present in elevated levels in Smith-Lemli-Opitz syndrome, were both significantly more strongly domain-promoting than cholesterol. Domain formation was also affected by the structure of the sphingolipid (or that of an equivalent "saturated" phospholipid) component. Sterols had pronounced effects on domain formation by sphingomyelin and dipalmitoylphosphatidylcholine but only a weak influence on the ability of cerebrosides to form domains. Strikingly it was found that a small amount of ceramide (3 mol %) significantly stabilized domain/raft formation. The molecular basis for, and the implications of, the effects of different sterols and sphingolipids (especially ceramide) on the behavior and biological function of rafts are discussed. |