| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits and cholesterol-fed rabbits Wajima, T., S. Makita, et al. (2004), Pharmacology 70(3): 123-9. Abstract: The aim of this study was to evaluate the effects of (+)-(E)-6S-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)e thenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (HR780), a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on hypercholesterolemia in Watanabe heritable hyperlipidemic (WHHL) rabbits and rabbits fed a diet with 1% cholesterol, in comparison with the effects of simvastatin. Each drug was administered orally to WHHL rabbits for 24 weeks and to 1% cholesterol-fed rabbits for 10 weeks. In WHHL rabbits, HR780 at doses of 1, 2.5 and 5 mg/kg/day reduced the plasma total cholesterol level by 15, 24 and 20%, respectively. In contrast, simvastatin at 5 mg/kg/day lowered the level by 23%. In 1% cholesterol-fed rabbits, HR780 (1 and 2.5 mg/kg/day) was found to inhibit the increases in the plasma total cholesterol and phospholipid levels and liver cholesterol contents in a dose-dependent manner. Simvastatin (5 mg/kg/day) also inhibited their increase. Neither HR780 nor simvastatin increased the contents of cholesterol and total bile acid in the gallbladder bile. In conclusion, long-term treatment with HR780 reduced the plasma cholesterol level in WHHL rabbits and 1% cholesterol-fed rabbits, and decreased the liver cholesterol contents in 1% cholesterol-fed rabbits. |
| Effects of hydrophobic and hydrophilic bile salt mixtures on cholesterol crystallization in model biles Venneman, N. G., S. J. Huisman, et al. (2002), Biochim Biophys Acta 1583(2): 221-8. Abstract: The hydrophilic bile salt ursodeoxycholate is frequently used to dissolve cholesterol gallstones. We have now quantitated crystallization as a function of bile salt hydrophobicity, phospholipid content, cholesterol saturation and total lipid concentration (TLCo). METHODS: Crystallization in supersaturated model biles with low phospholipid contents (left two-phase-micelles and crystal-containing-zone) was assessed during 21 days by microscopy and chemical measurement of crystal mass. For model biles with higher phospholipid contents (central three-phase-micelles, vesicles and crystal-containing-zone), lipid distribution into various phases was determined by combined ultracentrifugation-filtration-dialysis methodology (Biochim. Biophys. Acta 1532 (2001) 15-27). RESULTS: In the left two-phase zone, crystal numbers and masses were highest in case of more hydrophilic bile salt composition (TUDC 100%>TC/TUDC 70%/30%>TC 100%>TC/TDC 70%/30%>TDC 100%) and decreased with increasing phospholipid contents, lower TLCo and lower cholesterol saturation index (CSI). In contrast, in the presence of vesicles (three-phase zone), crystallization decreased at increasing bile salt hydrophilicity, with concomitant increased vesicular cholesterol solubilization. CONCLUSIONS: Presence of vesicular phases is a prerequisite for inhibition of cholesterol crystallization by tauroursodeoxycholate. |
| Effects of hydroxyl radicals low density lipoprotein and cholesterol on the calcium responding behavior of vascular endothelial cells Feng, X., L. Yuan, et al. (2003), Beijing Da Xue Xue Bao 35(6): 613-7. Abstract: OBJECTIVE: To investigate the effects of hydroxyl radicals, low density lipoprotein and cholesterol on the response of vascular endothelial cells to the change in extracellular calcium ion concentration. METHODS: After treatment with the above mentioned atherogenic factors respectively, the cells were loaded with Fluo-3 and then the response of the cells to the increase in extracellular Ca(2+) was observed under a confocal laser scanning microscope. RESULTS: Normal vascular endothelial cells were sensitive to the increase in extracellular Ca(2+). The free calcium ions in cytosol increased pulsively until a maximum was reached, and then was reduced to the initial level rapidly. Treatment with hydroxyl radicals produced by Fe(2+)-EDTA made the cells rather slow to the change in extracellular Ca(2+). A morphological examination showed that some damage to the cells was caused. After cultivation with low density lipoprotein (0.10 g x L(-1)), the cells lost most of their capability to modulate intracellular calcium ion and thus the calcium level remained high at the end of the experiment. If a hydroxyl radical treatment preceded the incubation with low density lipoprotein, a more serious damage was observed. Some of the cells were caused to death while the extracellular Ca(2+) increased. Upon exposing to a higher level of extracellular calcium ion, the cytosol Ca(2+) did not increase; contrarily, it decreased gradually. The hydroxyl radical oxidation followed by cholesterol treatment made the cells respond disorderly to the increase in extracellular Ca(2+), indicating that rather serious damage had been caused to the cells. CONCLUSION: These findings indicate that hydroxyl radicals, low density lipoprotein and cholesterol interfere with the response of vascular endothelial cells to extracellular calcium ions. This may be one of the ways these factors contribute to the initiation and development of atherosclerosis. |
| Effects of hyodeoxycholic acid and alpha-hyocholic acid, two 6 alpha-hydroxylated bile acids, on cholesterol and bile acid metabolism in the hamster Cohen-Solal, C., M. Parquet, et al. (1995), Biochim Biophys Acta 1257(2): 189-97. Abstract: The effects of hyodeoxycholic (HDCA) and alpha-hyocholic acids (alpha-HCA), on cholesterol, bile acid and lipoprotein metabolism, were studied in hamsters. The animals were fed a low cholesterol control diet supplemented with 0.1% HDCA or alpha-HCA for 3 weeks. In both treated groups, the LDL-cholesterol concentration was significantly lowered and was associated with a global hypocholesterolemic effect. Moreover, hepatic cholesterol ester storage was reduced and HMGCoA reductase activity was respectively enhanced 13.5-times and 7.7-times in HDCA and alpha-HCA groups compared to controls. In contrast, cholesterol 7 alpha-hydroxylase activity and LDL-receptor activity and mass were not modified. In bile, the cholesterol saturation index was increased 5-fold (HDCA group) and 2-fold (alpha-HCA group) as a consequence of an enlarged proportion of biliary cholesterol. The two 6-hydroxylated bile acids induced an enhanced fecal excretion of neutral sterols (HDCA group: 11.6-times, alpha-HCA group: 3.2-times versus controls) which was consistent with a 59% decrease in intestinal cholesterol absorption in the HDCA group. The major effects due to bile acid treatments were a decrease in LDL-cholesterol concentration, a strong stimulation of hepatic cholesterol biosynthesis and an excessive loss of cholesterol in feces. These perturbations might be the result of the enrichment of bile with hydrophilic bile acids, leading to a limited return of endogenous cholesterol from the intestine to the liver. |
| Effects of hyperlipidemia on aortic endothelial cell turnover and transendothelial macromolecular transport in cholesterol-fed rats Lin, S. J. and Y. Z. Ding (1996), Zhonghua Yi Xue Za Zhi (Taipei) 58(4): 235-40. Abstract: BACKGROUND: Hyperlipidemia, hypertension, cigarette smoking and diabetes are some major risk factors for atherosclerosis and cardiovascular disease. Repeated endothelial injury and enhanced focal intimal influx of plasma lipoproteins are the pivotal mechanisms involved in atherogenesis. We previously demonstrated that the endothelial cell turnover and associated endothelial permeability were significantly increased in the aorta of spontaneously hypertensive rats, chronic oral nicotine-treated rats, and streptozotocin-diabetic rats. In the present investigation, we examined the effects of hyperlipidemia on arterial endothelial cell turnover and transendothelial macromolecular transport in cholesterol-fed rats. METHODS: Sixteen male Sprague-Dawley rats were fed a diet containing 5% cholesterol for 6 weeks. A group of 14 agematched rats fed a regular diet and maintained over the same time period, were served as the controls. In en face preparations of the thoracic aorta, mitotic endothelial cells were identified by hematoxylin staining, IgG-containing dead endothelial cells were identified by an indirect immunoperoxidase method, and endothelial leakage to Evans blue-albumin complexes was quantified by fluorescence microscopy. RESULTS: The results showed that plasma cholesterol and triglyceride levels were higher in cholesterol-fed rats. The hyperlipidemic rats, compared to control rats, had higher values for the frequency of endothelial cell death (1.08 +/- 0.28% vs 0.75 +/- 0.16%), the frequency of endothelial cell mitosis (0.015 +/- 0.005% vs 0.013 +/- 0.003%) and the number density of Evans blue-albumin leaky foci (6.19 +/- 0.64/mm2 vs 5.23 +/- 0.76/mm2) in the aorta. CONCLUSIONS: Similar to the situations in hypertension, nicotine consumption and diabetes, the observed trend of increases in the frequency of endothelial cell turnover and endothelial permeability to large molecules in the aorta of cholesterol-fed rats suggested that these changes may contribute to accelerated atherogenesis in hyperlipidemia. However, since rat is not a favored animal model for studies of dietinduced hyperlipidemia and atherosclerosis, further investigations using other animal models such as rabbit, are needed to verify these observations. |
| Effects of hypothyroidism and high-fat feeding on mRNA concentrations for the low-density-lipoprotein receptor and on acyl-CoA:cholesterol acyltransferase activities in rat liver Salter, A. M., R. Hayashi, et al. (1991), Biochem J 276 (Pt 3): 825-32. Abstract: 1. Induction of hypothyroidism in rats by feeding propylthiouracil (PTU) significantly increased serum cholesterol concentrations, and the effect was more pronounced for cholesterol in low-density lipoproteins (LDL) rather than high-density lipoproteins (HDL). The concentrations of serum triacylglycerol were decreased in hypothyroidism. These effects on serum lipids were also seen when the normal rats were pair-fed with the PTU-treated group. 2. Feeding a diet rich in saturated fat and cholesterol further increased cholesterol concentrations in LDL and also elevated that in very-low-density lipoprotein (VLDL) of hypothyroid rats. In euthyroid rats such a diet resulted in a relatively small increase in VLDL cholesterol, whereas LDL cholesterol was decreased. 3. Steady-state concentrations of mRNA for the hepatic LDL receptor were significantly decreased in the livers of hypothyroid rats, but were not significantly changed by high-fat feeding in euthyroid or hypothyroid rats. 4. The expression of the LDL receptor in hepatocytes cultured from hypothyroid rats was decreased relative to the euthyroid controls. 5. Whereas the esterification of cholesterol with oleate in hepatocytes cultured from hypothyroid rats was decreased, the activity of acyl-CoA:cholesterol acyltransferase (ACAT) in the livers of these animals was not changed. 6. High-fat feeding increased the hepatic ACAT activity in normal and hypothyroid rats. 7. Incubation of rat hepatocytes with 10 nM-tri-iodothyronine for 4 h increased the relative concentration of the mRNA for the LDL receptor by 25%. 8. It is therefore concluded that thyroid hormones stimulate the synthesis and expression of the hepatic LDL receptor. Elevated cholesterol concentrations in LDL in hypothyroidism probably result from a primary defect in the expression of the hepatic receptor, rather than indirectly via changes in ACAT activity. |
| Effects of hypoxia on cholesterol metabolism in human monocyte-derived macrophages Matsumoto, K., T. Taniguchi, et al. (2000), Life Sci 67(17): 2083-91. Abstract: We assessed the metabolism of low density lipoprotein (LDL) of human monocyte-derived macrophages under hypoxia. The specific binding and association of 125I-labeled LDL (125I-LDL) were not changed under hypoxia compared to normoxia. However, the degradation of 125I-LDL under hypoxia decreased to 60%. The rate of cholesterol esterification under hypoxia was 2-fold greater on incubation with LDL or 25-hydroxycholesterol. The cellular cholesteryl ester content was also greater under hypoxia on incubation with LDL. Secretion of apolipoprotein E into the medium was not altered under hypoxia, suggesting that apolipoprotein E independent cholesterol efflux may be reduced under hypoxia. Thus, hypoxia affects the intracellular metabolism of LDL, stimulates cholesterol esterification, and enhances cholesteryl ester accumulation in macrophages. Hypoxia is one of the important factors modifying the cellular lipid metabolism in arterial wall. |
| Effects of hypoxia on sterol synthesis, acyl-CoA:cholesterol acyltransferase activity, and efflux of cholesterol in cultured rabbit skin fibroblasts Mukodani, J., Y. Ishikawa, et al. (1990), Arteriosclerosis 10(1): 106-10. Abstract: To elucidate the mechanisms of cholesterol accumulation in cells under hypoxic conditions, we tested the effects of hypoxia on sterol synthesis, on the activity of acyl-CoA:cholesterol acyltransferase (ACAT), and on the efflux of cholesterol in cultured rabbit skin fibroblasts. Sterol synthesis was measured by the incorporation of 14C-acetate into sterol, and ACAT activity, by the incorporation of 14C-oleate into cholesteryl ester. Hypoxia suppressed both sterol synthesis and the efflux of cholesterol but increased ACAT activity. These results suggest that hypoxia disturbs the balance of cholesterol metabolism in cells and induces intracellular lipid accumulation. |
| Effects of ileo-rectal anastomosis on cholesterol metabolism in pigs fed either casein or extruded soya beans Bento, O. P., J. M. Martins, et al. (2004), Br J Nutr 91(5): 689-98. Abstract: The importance of legume proteins in cholesterol metabolism has been recognised, but the hindgut contribution is still unclear. The present work was undertaken to address the role of the caecum-colon in cholesterol metabolism in intact (I) and ileo-rectal anastomosed (IRA) pigs fed with casein or extruded soyabean (ES) diets. Four groups of six growing pigs were assigned to the treatments (casein-I, casein-IRA, ES-I, ES-IRA) for 3 weeks. Plasma total cholesterol, LDL- and HDL-cholesterol were not modified by surgery or diet. In the liver, the ES diet significantly depressed non-esterified, esterified and total cholesterol. The treatments did not affect hepatic 3-hydroxy-3-methylglutaryl CoA reductase, cholesterol 7alpha-hydroxylase or sterol 27-hydroxylase activities. In the gallbladder bile of ES-fed pigs, total cholesterol was depressed while total bile acid concentration was increased. IRA and the ES diet markedly decreased the biliary bile acid microbial metabolites (namely hyodeoxycholic acid) and increased the primary bile acids (mainly hyocholic acid). The concentration of bile hydrophobic acids was decreased only by the ES diet. Faecal neutral sterol output was increased in ES-fed pigs, but the bile acid and the sum of neutral and acidic steroid outputs were not. Microbial transformation of neutral and acidic steroids was markedly reduced by IRA, especially in the ES-fed pigs. Thus, surgery and ES modulated the steroid profile but the caecum-colon did not seem to play a crucial role in determining cholesterolaemia in pigs. |
| Effects of ileum transplantation and chronic rejection on absorption and synthesis of cholesterol in pigs Pakarinen, M. P., P. Kuusanmaki, et al. (2003), Pediatr Surg Int 19(9-10): 656-61. Abstract: We investigated the effects of ileum allotransplantation and chronic graft rejection on the synthesis and absorption of cholesterol. Twenty pigs underwent intestinal transection or ileum transplantation, in which the distal half of the jejunoileum was replaced with an ileal autograft or allograft. Conventional triple therapy with cyclosporine (10 mg/kg per day), azathioprine and methylprednisolone was tapered to cyclosporine (5 mg/kg per day) after 10 weeks. Serum lathosterol and campesterol, respective markers of cholesterol synthesis and absorption, were determined and related to graft histology. When compared to transected controls, auto- and allotransplantation of ileum similarly increased (P<0.05) lathosterol and decreased (P<0.01) campesterol for 12 weeks, despite normal graft histology. Chronic graft rejection progressed between 12 and 18 weeks, when a further increase in lathosterol (+104%) and decrease in campesterol (-67%) was observed. Obliteration of mesenterial arteries in chronically rejecting grafts was associated with high cholesterol synthesis (R=0.975, P=0.0512). Auto- and allotransplantation of the ileum similarly modulate synthesis and absorption of cholesterol in pigs with non-rejecting grafts. Chronic rejection of the ileal graft appears to markedly increase cholesterol synthesis, which may primarily result from impaired ileal reabsorption of bile acids due to gradual obliteration of mesenterial arteries (chronic rejection). Serial measurements of cholesterol synthesis and bile acid absorption may prove to be a useful tool in the diagnosis of chronic rejection-associated small intestinal graft dysfunction. |
| Effects of including soy protein in a blood cholesterol-lowering diet on markers of cardiac risk in men and in postmenopausal women with and without hormone replacement therapy West, S. G., K. F. Hilpert, et al. (2005), J Womens Health (Larchmt) 14(3): 253-62. Abstract: BACKGROUND: Increased consumption of soy foods has been associated with reduction in low density lipoprotein cholesterol (LDL-C) in both clinical and observational studies. However, it is not clear whether adding soy to a low-fat diet has additional lipid-lowering benefits, and few previous studies have examined these effects in women using hormone replacement therapy (HRT+). METHODS: We tested whether adding soy protein to a low-fat, high-fiber, Step I diet improved cardiac risk markers in 18 postmenopausal women and 14 men with hypercholesterolemia and examined whether concurrent use of HRT altered diet responsiveness. Diets were matched for macronutrient content, and all food was provided. After 3 weeks on the Step I diet, subjects were randomized to diets (6 weeks) containing 25 g/day protein isolate from soy or cow's milk, with crossover. The soy treatment contained 90 mg/day isoflavones. Lipids, vascular cell adhesion molecule-1 (VCAM-1), p-selectin, and urinary isoflavonoids were measured at the end of each diet. Results: In men and HRT- women only, there were significant reductions in LDL-C (-17.3%), high-density lipoprotein cholesterol (HDL-C) (-15.3%), and triglycerides (-11.5%) during the Step I diet, and soy had no additional effects. At study entry, HRT+ women had lower LDL-C and higher triglycerides than men. Their LDL-C was unchanged, and triglycerides were significantly reduced (-15.1%) by the Step I diets. Isoflavonoid excretion was unrelated to diet response or HRT status. CONCLUSIONS: In men and HRT- women, the diets significantly lowered LDL-C, independent of soy intake. In HRT+ women, the diets improved triglycerides without lowering HDL-C. |
| Effects of increasing amounts of dietary cholesterol on postprandial lipemia and lipoproteins in human subjects Dubois, C., M. Armand, et al. (1994), J Lipid Res 35(11): 1993-2007. Abstract: Our aim was to determine the effects of increasing amounts of dietary cholesterol (0-710 mg) on the postprandial plasma lipid responses and lipoprotein changes in normolipidemic human subjects. Ten subjects were fed five different test meals in a random order: one meal did not contain fat or cholesterol while the four others contained a fixed amount of lipids (45 g) and 0, 140, 280, and 710 mg cholesterol, respectively. Fasting and post-meal blood samples were obtained for 7 h. Large and small triglyceride-rich lipoproteins (TRL), low density (LDL), and high density (HDL) lipoproteins were isolated. Compared to the no-fat, no-cholesterol meal, the fat-enriched meals raised (P < 0.05) plasma triglycerides, phospholipids, and free cholesterol and lowered cholesteryl esters postprandially. The meals containing zero or 140 mg cholesterol generally elicited comparable postprandial plasma and lipoprotein lipid responses. The meals providing 280 or 710 mg cholesterol significantly increased postprandial plasma phospholipids and large TRL triglycerides and decreased plasma esterified cholesterol. The lipid composition of the large TRLs and the concentrations of the small TRL lipid components were not altered postprandially by cholesterol intake. On the other hand, LDL free cholesterol increased after 3 h, LDL cholesteryl esters dropped after 3 and 7 h, HDL cholesteryl esters dropped after 3 h, and HDL phospholipids increased 7 h after ingesting meals highly enriched in cholesterol. Blood insulin, apoA-I and apoB were not altered postprandially by cholesterol intake. Thus, the data show that ingesting more than 140 mg cholesterol per meal significantly alters the postprandial lipoprotein response in healthy subjects. |
| Effects of indapamide on atherosclerosis development in cholesterol-fed rabbits Del Rio, M., T. Chulia, et al. (1995), J Cardiovasc Pharmacol 25(6): 973-8. Abstract: We examined the effect of indapamide (IND) on the development of atherosclerosis lesions in rabbits maintained on a 1% (wt/wt) cholesterol-enriched diet for a 16-week period. IND was supplemented to the diet at three different levels to correspond to doses of 0.1, 0.3, and 1 mg/kg/day. Throughout the treatment, dietary consumption and body weight gains were comparable among the experimental and control groups. IND had no significant effect on plasma cholesterol, triglycerides, or phospholipids concentrations. Despite the lack of effect of the drug on these parameters, its administration produced a tendency toward a reduction in the aortic content of cholesterol and a dose-dependent and significant decrease in aortic damage. In the aortic arch, the extent of intimal aortic surface covered by grossly discernible atherosclerotic lesions was decreased by IND 1 mg/kg/day from 11.02 +/- 1.10 to 6.00 +/- 1.00% (p < 0.05) and from 9.72 +/- 1.39 to 5.37 +/- 1.20% (p < 0.05) in the remaining thoracic sections. In addition, the former dose also reduced the number of lesions per square centimeter from 3.69 +/- 0.68 to 1.72 +/- 0.53% (p < 0.05), and from 3.37 +/- 0.85 to 1.55 +/- 0.46% (p < 0.05) in aortic arch and in thoracic sections, respectively. The possibility that IND reduces the development of atherosclerotic lesions produced by diet-induced hypercholesterolemia through a mechanism involving its calcium antagonist and/or its antioxidant activity is discussed. |
| Effects of infant nutrition on cholesterol synthesis rates Cruz, M. L., W. W. Wong, et al. (1994), Pediatr Res 35(2): 135-40. Abstract: Nutrient effects on cholesterol fractional synthesis rates (FSR) in infancy by stable isotope determination have not been studied. We hypothesized that FSR is significantly reduced with high dietary cholesterol and phytoestrogen intake and increased with low dietary cholesterol and phytoestrogen intake. We prospectively studied 33 term male infants exclusively fed human milk (high cholesterol, low phytoestrogen, n = 12), cow milk-based formula (low cholesterol, low phytoestrogen, n = 8), soy milk-based formula (zero cholesterol, high phytoestrogen, n = 7), or soy milk-based formula modified to contain cholesterol (low cholesterol, high phytoestrogen, n = 6) during the first 4 mo of life. Cholesterol FSR was determined from rate of incorporation of deuterium into erythrocyte membrane cholesterol, and urinary isoflavone excretion (an index of dietary phytoestrogen exposure) was measured by gas chromatography-mass spectrometry. Significant differences in cholesterol FSR were found. FSR (%/d) was lowest in human milk (2.62 +/- 0.38), highest in soy milk-based formula (9.40 +/- 0.51), and intermediate in cow milk-based and modified soy milk-based formula (6.90 +/- 0.48 and 8.03 +/- 0.28, respectively), p < 0.0001. Cholesterol FSR was significantly lower in modified soy milk-based compared with soy milk-based formula, p < 0.05. We also show for the first time that dietary phytoestrogens are absorbed and excreted by the infant fed soy protein-based formula. Urinary isoflavone excretion was inversely related to cholesterol FSR, but it was not significantly related to serum cholesterol concentration. We conclude that the type of infant nutrition and dietary cholesterol are major factors influencing cholesterol fractional synthesis rates in infancy. |
| Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men Gylling, H. and T. A. Miettinen (1996), J Lipid Res 37(8): 1776-85. Abstract: Effectiveness of a simultaneous inhibition of cholesterol absorption and synthesis, caused by sitostanol ester margarine and pravastatin, was studied to control mild hypercholesterolemia in men with non-insulin-dependent diabetes mellitus (NIDDM) (n = 8). Margarine, 24 g daily, was a basal dietary treatment. Four 7-week intervention periods included margarine, sitostanol (3 g/day) ester margarine, pravastatin (40 mg/day), and sitostanol ester margarine plus pravastatin in a random order. Pravastatin lowered serum total (-32%) and LDL cholesterol (-38%) and apolipoprotein B (-39%) because of enhanced removal (+20%) and decreased production (-26%) of LDL apolipoprotein B, and reduced synthesis (-9%) and turnover (-8%) of cholesterol, which resulted in reduced biliary cholesterol seretion (-18%). Even though serum triglycerides were lowered by 28%, VLDL, IDL, and light and dense LDL became triglyceride-enriched. Despite increasing cholesterol synthesis, sitostanol lowered LDL cholesterol (-14%) by inhibiting cholesterol absorption (-68%) and LDL apolipoprotein B production rate (-20%). Combination of pravastatin and sitostanol ester lowered serum total, VLDL, IDL, and LDL cholesterol and LDL apolipoprotein B by the highest rate, 35%, 50%, 35%, 44%, and 45% from the control margarine period, respectively, because of reduced apolipoprotein B transport rate (but unchanged removal), in both the total and dense LDL subfractions. HDL cholesterol and apolipoprotein A-I kinetics were unchanged. In spite of decreased absorption, cholesterol synthesis was not compensatorily increased. In conclusion, simultaneous inhibition of cholesterol absorption and synthesis lowers LDL cholesterol and apolipoprotein B by 44-45% solely through inhibition of LDL apolipoprotein B production rate in hypercholesterolemic NIDDM patients. A combination of statin to sitostanol ester margarine-resistant patients offers a safe and effective measure to normalize abnormally high cholesterol values, probably with a lowered statin dose. |
| Effects of insulin on cholesterol synthesis in type II diabetes patients Scoppola, A., G. Testa, et al. (1995), Diabetes Care 18(10): 1362-9. Abstract: OBJECTIVE: To evaluate the effects of intensive insulin therapy and subsequent optimized metabolic control on daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, and the acute effects of insulin on plasma MVA concentrations in type II diabetes. RESEARCH DESIGN AND METHODS: Ten (five men and five postmenopausal women) nonobese, normolipidemic (total cholesterol < 6.2 mmol/l, triglycerides < 2.82 mmol/l), type II diabetic patients in poor metabolic control (HbA1c > 10%, fasting plasma glucose > 11 mmol/l) and receiving sulfonylurea treatment were selected. The 24-h urinary MVA excretion and plasma lipid values were determined before and after intensive insulin therapy. The acute effects of insulin on plasma MVA concentrations were also evaluated during a 3-h euglycemic hyperinsulinemic clamp study. RESULTS: Urinary MVA excretion rates (mumol/24h) were 1.82 +/- 0.21 in control subjects and 2.49 +/- 0.35 (P < 0.01 vs. control subjects) and 1.78 +/- 0.28 in patients before and after intensive insulin therapy, respectively. Total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides decreased by 9, 8, and 12%, respectively, after blood glucose optimization. Acute insulin infusion during the euglycemic clamp studies reduced mean plasma MVA concentrations at 120 and 180 min by 29 and 38%, respectively (P < 0.01 for both vs. baseline). CONCLUSIONS: Our study demonstrates that in nonobese, normolipidemic, type II diabetic patients under poor metabolic control, an increased cholesterol synthesis is normalized by insulin therapy. Hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of MVA, the immediate product of hydroxymethylglutaryl-CoA reductase activity and an index of whole-body cholesterol synthesis. |
| Effects of interactions of apolipoprotein A-II with apolipoproteins A-I or A-IV on 3Hcholesterol efflux and uptake in cell culture Stein, O., Y. Dabach, et al. (1995), Biochim Biophys Acta 1257(2): 174-80. Abstract: Conflicting evidence has accumulated with years regarding the putative negative effect of apolipoprotein A-II on apo A-I mediated cholesterol efflux. In this study, this question was reexamined and in addition to the interaction of apo A-II with apo A-I, its possible effect on apo E and apo A-IV was investigated as well. Free cholesterol (FC) donors were the main components of atheroma, namely, mouse peritoneal macrophages (MP), bovine aortic smooth muscle (SMC) and fibroblasts labeled with 3HFC. Acceptors of FC were dioleoylphosphatidylcholine (DOPC) liposomes containing apo A-I, rh-apo A-IV or rh-apo E alone or together with apo A-II. When 3HFC labeled MP were incubated for 2 or 4 h with equimolar concentrations of apo A-I, A-II, A-IV or E, the lowest 3Hcholesterol efflux occurred with apo A-II. Exposure of 3HFC MP to liposomes containing apo A-I/A-II at 1:2 M/M (keeping the total protein concentration at 50 micrograms/ml), resulted in a lower 3HFC efflux as compared to apo A-I alone. However, when apo A-I or apo A-IV protein concentration was kept constant and supplemented with apo A-II, a lower 3HFC efflux was found only at 1:3 M/M of apo A-I/A-II. Apo A-II added to apo E had no effect on FC efflux. With aortic SMC and fibroblasts, no inhibitory effect of addition of apo A-II to apo A-I or apo A-IV on cholesterol efflux was seen at apo A-I/A-II of 1:1 or 1:2 M/M. The uptake of macrophage derived 3HFC by SMC or HepG2 cells was studied using the serum-free efflux media, containing PC liposomes + apolipoproteins, from 3H-labeled macrophages. The cellular uptake of 3HFC was higher when apo A-II had been added to apo A-I or apo A-IV than when the apolipoproteins were added alone. In conclusion, apo A-II was found to be less effective in cholesterol efflux and to interfere with the action of A-I only when the cholesterol donors were macrophages and when the relative amount of apo A-I to apo A-II was low. This was not the case when SMC or fibroblasts served as cholesterol donors. In the presence of apo A-II, enhanced 3Hcholesterol delivery to cells was seen which could contribute to the proatherogenic activity of apo A-II. |
| Effects of intervention on compliance to referral and lifestyle recommendations given at cholesterol screening programs Gans, K. M., K. L. Lapane, et al. (1994), Am J Prev Med 10(5): 275-82. Abstract: To enhance compliance to physician referral as well as dietary and other lifestyle recommendations given at blood cholesterol (BC) screening programs, we randomized Pawtucket Heart Health Program SCORE (screening, counseling, referral event) participants with elevated BC levels into one of four groups: usual care group; a participant intervention group (mailed reminder letter and refrigerator magnet); a physician intervention group (mailed packet to participant's physician including letter, National Cholesterol Education Program NCEP guidelines, and preaddressed postcard to mail to patient); and a group that received both interventions. Beginning four months after the screening, we surveyed study subjects by phone. The participant intervention increased recall of physician referral and dietary recommendations; however, neither intervention successfully improved compliance to referral or dietary and lifestyle recommendations. Overall, 58%, 67% and 34% of subjects reported complying to physician referral, dietary recommendations, and lifestyle recommendations, respectively. Referral compliance was associated with a longer time interval between screening and survey (relative risk RR = 1.3, 95% confidence interval CI= 1.0, 1.7), possession of medical insurance that covered physician visits (RR = 2.1, 95% CI = 0.98, 4.4), and history of hypertension (RR = 2.6, 95% CI = 1.1, 5.8). Dietary compliance was positively associated with baseline BC levels > or = 240 mg/dL (RR = 3.3, 95% CI = 1.4, 7.3) and negatively associated with increasing age; each one year increase in age corresponded to a 3% decrease in compliance (RR = 0.97, 95% CI = 0.9. 1.0).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Effects of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death Kellner-Weibel, G., W. G. Jerome, et al. (1998), Arterioscler Thromb Vasc Biol 18(3): 423-31. Abstract: This study was designed to identify cellular responses associated with free cholesterol (FC) accumulation in model macrophage foam cells. Mouse peritoneal macrophages (MPMs) or J774 macrophages were loaded with cholesteryl esters using acetylated LDL and FC/phospholipid dispersions and were subsequently exposed to an acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor. This treatment produced a rapid accumulation of cellular FC. The FC that accumulated due to ACAT inhibition was more readily available for efflux to 2-hydroxypropyl-beta-cyclodextrin (which removes cholesterol from the plasma membrane) than FC in untreated control cells. After a 3-hour exposure to an ACAT inhibitor, a significant increase in phospholipid synthesis was seen, followed by the leakage of LDH after 12 hours of treatment. We also observed, by electron and fluorescence microscopy, morphological indications of both apoptosis and necrosis in cells treated with an ACAT inhibitor. In addition, inhibition of ACAT for 48 hours resulted in the formation of FC crystals in MPMs but not in J774 cells. If compound 3beta-2-(diethylamino)ethoxyandrost-5-en-17-one (U18666A), which modulates intracellular trafficking of cholesterol, was added together with the ACAT inhibitor, each of the metabolic changes elicited by the accumulation of excess FC was either diminished or eliminated. The protective affect of U18666A was not due to a decrease in cellular FC concentrations, because cells treated with an ACAT inhibitor accumulated similar amounts of FC in the presence or absence of U18666A. Thus, treatment with U18666A results in the sequestering of FC in a pool that prevents it from causing various responses to FC deposition in macrophages. The metabolic changes that were produced when these model foam cells were treated with the ACAT inhibitor parallel the pathological events that have been shown to occur in the developing atherosclerotic plaque. |
| Effects of intravenous injection and intraperitoneal continual administration of sodium propionate on serum cholesterol levels in rats Kishimoto, Y., S. Wakabayashi, et al. (1995), J Nutr Sci Vitaminol (Tokyo) 41(1): 73-81. Abstract: To examine the effects of sodium propionate on serum cholesterol levels, rats were given sodium propionate intravenously and intraperitonealy. Six-week-old male Sprague-Dawley rats were kept on a cholesterol-free semisynthetic diet for 2 weeks, fasted, and given 400 microliters of saline solution intravenously supplemented with 0.01-10 mg sodium propionate. Three hours after injection of 1 mg of sodium propionate, the serum total-cholesterol level was significantly reduced (85.4 +/- 4.0 mg/dl) compared with its starting level (102 +/- 3.4 mg/dl), with the reducing effect lasting for 24 h. The intensity of the reduction increased proportionately with increased sodium propionate concentrations from 0.01 to 1 mg. Next, to evaluate the influence of continual sodium propionate administration on serum cholesterol levels, 6-week-old male rats were implanted with an osmotic pump intraperitonealy (ALZET Model 2ML2, pumping rate: 5.0 microliter/h; duration: 14 days; reservoir volume: 2,000 microliters). At day 14, serum total-cholesterol levels were reduced by continual sodium propionate administration at both 0.12 and 1.2 mg/day. The maximum percentage change in the serum total-cholesterol level was 78.5 +/- 6.7% of its starting level (111 +/- 7.1 mg/dl), observed at 1.2 mg/day at day 7. These results indicate that sodium propionate can reduce serum total-cholesterol levels in vivo. |