| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of growth hormone on hepatic cholesterol metabolism. Lessons from studies in rats and humans Rudling, M., P. Parini, et al. (1999), Growth Horm IGF Res 9 Suppl A: 1-7. |
| Effects of growth hormone on mammary cholesterol metabolism in the lactating rat Shand, J. H., D. W. West, et al. (1995), Biochem Soc Trans 23(4): 579S. |
| Effects of guava intake on serum total and high-density lipoprotein cholesterol levels and on systemic blood pressure Singh, R. B., S. S. Rastogi, et al. (1992), Am J Cardiol 70(15): 1287-91. Abstract: There is evidence that inclusion of high fiber foods such as oats, fruits and vegetables in the diet can decrease fat intake and modulate blood lipids. To test this hypothesis, 61 group A and 59 group B patients with essential hypertension were administered guava fruit preferably before meals in a foods-to-eat approach rather than foods-to-restrict, in a randomized and single-blind fashion for 12 weeks. At entry into the study, mean age, male sex, mean body mass index, percentages of risk factors and mean levels of blood lipids were comparable between groups A and B. Adherence to guava consumption was assessed by questionnaires and weighing of guava intake by 24-hour recall after 12 weeks of follow-up. Nutrient intakes including saturated and total fat were significantly decreased; carbohydrates, total and soluble fiber and vitamins and mineral intakes were significantly higher in group A than in group B at 12 weeks. There was a significant net decrease in serum total cholesterol (9.9%), triglycerides (7.7%) and blood pressures (9.0/8.0 mm Hg) with a significant net increase in high-density lipoprotein cholesterol (8.0%) after 12 weeks of guava fruit substitution in group A than in group B. By adding moderate amounts of guava fruit in the usual diet, changes in dietary fatty acids and carbohydrates may occur, providing significant amounts of soluble dietary fiber and antioxidant vitamins and minerals without any adverse effects. There is a greater decrease in lipoprotein metabolism and blood pressures. |
| Effects of heparan-sulphate administration on clotting parameters and serum thromboxane B2 levels in cholesterol fed rabbits Restori, G., L. Boiardi, et al. (1992), Recenti Prog Med 83(1): 1-6. Abstract: We evaluated the effects of heparan-sulphate administration on clotting times, thromboelastographic parameters and serum thromboxane B2 levels in hypercholesterolemic rabbits with aortic atherosclerotic lesions (sudanophilic areas). 24 New Zealand male rabbits were divided into three groups of 8 animals each. Group A and B were fed a rabbit chow diet containing 0.7% of cholesterol whereas Group C was fed a standard rabbit diet without cholesterol. Group A was treated by subcutaneous route with 6 mg/kg/day of heparan sulphate. At the beginning of the study and after 3 and 6 months of treatment, serum cholesterol and thromboxane B2 levels were tested. Furthermore, at the end of the experiment, we evaluated plasma fibrinogen, aPTT, PT and TT values. The administration of heparan-sulphate in cholesterol fed rabbits produced: a reduction of plasma fibrinogen levels, without modifying aPTT and TT; a protective effect vs the lengthening in PT values, likely induced by cholesterol rich diet; a reduction of plasma thrombophilic activities and of aortic atheromasic involvement induced by dietetic cholesterol intake. However, increased serum thromboxane B2 levels, likely through a proaggregant activity were observed. We suggest that heparan-sulphate administration, in cholesterol fed rabbits, has a favourable effect on clotting parameters, while contrasting effects were found on platelet activity. |
| Effects of hepatic HDL-related mRNAs on plasma prebeta HDL in cholesterol-fed rabbits Sugano, M., N. Makino, et al. (1997), Artery 22(4): 182-205. Abstract: This study was undertaken to determine; 1) the effect of cholesterol enriched diet on prebeta-migrating (prebeta) HDL levels, 2) the effect of the diet on plasma proteins and/or activities likely associated with prebeta HDL (cholesteryl transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT) and apolipoprotein (apo)A-I), 3) the effect of the diet on the corresponding hepatic mRNAs and 4) the correlation between the hepatic mRNAs and prebeta HDL. Rabbits were fed 0.1% (low) cholesterol (LC group, n = 6) or 0.5% (high) cholesterol diet (HC group, n = 6) for 6 weeks. Plasma CETP activities, plasma total apoA-I and prebeta apoA-I concentrations in the HC group were significantly increased (58.95 +/- 2.37%, 191.52 +/- 13.93 mg/dl, 44.21 +/- 1.14 mg/dl, respectively) compared with the LC group (39.36 +/- 3.62%, 152.85 +/- 8.61 mg/dl, 30.12 +/- 2.79 mg/dl, respectively)(p < 0.05). Plasma LCAT activities did not differ significantly (56.65 +/- 7.19 vs 57.41 +/- 8.21; HC vs LC). Hepatic CETP, LCAT and apoA-I mRNA levels were determined using reverse transcription polymerase chain reaction (RT-PCR). Hepatic CETP mRNA levels, compared to GAPDH mRNA levels as a control, were increased in the HC group (2.226 +/- 0.115) compared with the LC group (1.649 +/- 0.170) (p < 0.05), while hepatic LCAT and apoA-I mRNA levels were unchanged. Thus, plasma concentration of prebeta HDL, CETP activity and the amount of hepatic CETP mRNA were increased in response to the dietary intake of cholesterol. Multiple regression analyses showed that only hepatic CETP mRNA levels had a positive correlation with plasma prebeta HDL concentration (p = 0.04). These results indicate that individual variations in hepatic CETP mRNA levels in rabbits fed a cholesterol diet probably has a major influence on the determination of plasma prebeta HDL concentration. |
| Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population Inazu, A., Y. Nishimura, et al. (2001), J Hum Genet 46(4): 172-7. Abstract: Genetic factors may play a major role in determining serum high-density lipoprotein (HDL) cholesterol (HDL-C) levels in the general population. Cholesteryl ester transfer protein (CETP) is a strong genetic factor as a determinant of HDL-C levels in Japanese, whereas hepatic lipase (HL) plays a predominant role in Caucasian populations. We investigated the effects of HL gene promoter polymorphisms on HDL-C levels in a general population of Japanese men (n = 299). An HL promoter polymorphism of -514C/T explained a considerable variance of HDL-C (2.9%), as compared with CETP mutations of D442G and IVS14 + 1G > A (3.6% and 1.9%). HL promoter variation of the -514C/C genotype, reported to have high HL activity, had significant effects on decreasing HDL-C levels (-3.8mg/dl), but -514T allele carriers had a weak effect on increasing HDL-C levels. The frequency of the -514T allele was three times higher (0.50) in the Japanese than in Caucasian populations (0.15-0.19). Thus, the higher frequency of the HL -514T allele, along with CETP gene mutations, could explain about 9% of phenotypic variability of HDL-C. These genetic attributes may be among the many factors that contribute to the relatively higher serum HDL-C levels in Japanese subjects. |
| Effects of high cholesterol and n-3 polyunsaturated fish oil diets on tissue and serum lipid composition in male rats Cameron, J. A., C. McCaskill, et al. (1995), Int J Vitam Nutr Res 65(3): 215-20. Abstract: The correlation between dietary cholesterol, high plasma lipids and cardiovascular disease is well recognized in many species. The purpose of the present study was to examine the effects of high cholesterol and moderately high fat intake of n-3 polyunsaturated fish oil diets on serum lipids in male rats. Male rats were fed either 21% menhaden oil (Control) or 21% menhaden oil with high (2%) cholesterol (MOC) for eight weeks. Whole blood was collected, and analyzed spectrophotometrically for serum cholesterol, triglycerides and lipoproteins. The selected tissues were carefully removed, weighed and analyzed for lipid profiles. The aortas were removed and lipogenesis determined. The results showed that except for spleen the total percent lipid content of heart, lung, liver, adrenal, kidney and brain was not affected in the MOC group. The percent fat content of spleen but not the weight was elevated by 4 fold compared to control. The hematocrit values in the MOC group were unaltered. Serum cholesterol was elevated by 62%, whereas the serum triglycerides and HDL cholesterol were unaltered in MOC group when compared to the MO control. High cholesterol feeding did not affect aortic lipogenesis in the MOC group compared to the control. These results suggest that cholesterol feeding along with n-3 polyunsaturated fish oil diet did not attenuate the anti-atherosclerotic effects of fish oil with the exception of serum cholesterol. |
| Effects of high cholesterol diet on gliosis in apolipoprotein E knockout mice. Implications for Alzheimer's disease and stroke Crisby, M., S. M. Rahman, et al. (2004), Neurosci Lett 369(2): 87-92. Abstract: Hypercholesterolemia has been suggested as a risk factor for Alzheimer's disease (AD). A genetic risk factor for AD is the E4 allele of apolipoprotein E (apoE). ApoE is the major lipoprotein transporter in the brain, and is mainly produced by glial cells. The present study is focussed on analysing the effects of high cholesterol (HC) diet, duration 9 months, on glial activation in the brain, both in wild type (WT) mice and in mice with a null mutation in the apoE gene (knock-out, KO) mice. The activation of astrocytes and microglia was analysed after immunohistochemical labelling of glial fibrillary acidic protein (GFAP), and F4/80, respectively. In addition, the expression of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) was analysed. There was a marked stimulation of astrocyte and microglial activation as well as induced expression of NQO1 in the hippocampus and cerebral cortex upon HC diet. Furthermore, there was significant astrocyte activation in the apoE KO mice, as compared to the WT mice, on ND. The long time exposure to HC diet combined with apoE deficiency resulted in a synergistic effect on the expression of NQO1 in the brain. |
| Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I Crouse, J. R., 3rd, J. Frohlich, et al. (1999), Am J Cardiol 83(10): 1476-7, A7. Abstract: A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins. |
| Effects of high fat-, cholesterol-enriched diet on the antioxidant defence mechanisms in the rabbit heart Lapenna, D., G. Del Boccio, et al. (1992), Free Radic Res Commun 17(2): 87-96. Abstract: In 7 rabbits fed on hyperlipidic diet (0.5% cholesterol, 5% peanut oil and 5% lard) for 4 weeks, the ventricular myocardium was tested for antioxidant defences and thiobarbituric acid reactive substances. Seven age-matched rabbits served as controls. The hearts were previously subjected to 45 min Langendorff perfusion to study coronary flow, developed tension and resting tension; coronary effluent values of CPK activity, pH and UV absorbance at 250 nm (i.e., low molecular weight ATP catabolites) were also investigated. After 4 weeks of diet, a significant rise of plasma cholesterol (P < 0.0001) and triglycerides (P < 0.0001) was observed. Total superoxide dismutase, catalase and glutathione transferase activities underwent a significant increase (P < 0.05) in the hyperlipidemic animals. On the contrary, a depression of glutathione reductase (P < 0.01) and selenium-dependent glutathione peroxidase (P < 0.01) activities, associated with decreased levels of non proteic thiol compounds (P < 0.01), was assessed. The selenium-independent glutathione peroxidase activity was not detectable in both groups. Thiobarbituric acid reactive substances levels were significantly increased in the hyperlipidemic rabbit myocardium (P < 0.01). Even though heart hemodynamics, CPK release and perfusate pH did not differ in control and experimental animals, higher 250 nm absorbance values (P < 0.05) were detected in the myocardial effluent of hyperlipidemic rabbits. In conclusion, high fat-, cholesterol-enriched diet induces an imbalance in the rabbit heart antioxidant defences, some of which are increased, whereas others are depressed, eventually resulting in enhanced myocardial lipid peroxidation. These biochemical changes are associated with higher perfusate values of UV absorbance at 250 nm, but not with significant CPK leakage or myocardial hemodynamics derangement. |
| Effects of high-cholesterol and atherogenic diets on vascular relaxation in spontaneously hypertensive rats Cappelli-Bigazzi, M., S. Rubattu, et al. (1997), Am J Physiol 273(2 Pt 2): H647-54. Abstract: Hypercholesterolemia is associated with more rapid development of atherosclerosis, and hypertension is frequently associated with abnormal vascular function. Therefore, to investigate the role of hypercholesterolemia and hypertension on vascular function, we studied three groups of male rats (aged 6 wk): normotensive Wistar-Kyoto rats (WKY) as a control group and spontaneously hypertensive rats (SHR) receiving either standard diet (SD; SHR-SD) or high-cholesterol (1%) diet (ChD; SHR-ChD). Vascular reactivity was tested on isolated aortic rings at 4 wk and at 3 and 6 mo of diet. At 3 mo, endothelium-dependent relaxation to acetylcholine (ACh) and ADP was significantly reduced in SHR-ChD but not in SHR-SD compared with WKY. At 6 mo, relaxations to ACh were further impaired in both SHR groups compared with WKY. Endothelium-independent vasodilation to nitroglycerin (NTG) was not different in the three groups of animals throughout 6 mo of diet. In additional experiments, we evaluated vascular reactivity in rats fed with ChD enriched with an excess of vitamin D atherogenic diet (AD) capable of producing vascular atherosclerotic lesions. In particular, we studied three additional groups of WKY and SHR rats fed with SD, AD, or AD plus a nonhypotensive dose of the calcium antagonist nitrendipine (Nit). Vasodilation to ACh and ADP was significantly blunted in WKY-AD compared with WKY-SD, whereas it was partially improved in WKY-Nit. There were no differences in endothelium-independent relaxation to NTG in the three WKY groups. In contrast, SHR-AD showed a marked reduction of endothelium-dependent and -independent vasodilation, but only endothelium-dependent vasodilation was preserved by addition of Nit to the diet. These data suggest that the development of vascular dysfunction in rat genetic hypertension is accelerated by ChD, in absence of detectable vascular lesions. Our study also shows that AD alters both vascular smooth muscle and endothelium-dependent relaxation. Low doses of Nit partially preserve endothelium-dependent vasodilation but do not affect the impairment of smooth muscle function in these rats. |
| Effects of high-cholesterol diet and parallel exercise training on the vascular function of rabbit aortas: a time course study Yang, A. L., C. J. Jen, et al. (2003), J Appl Physiol 95(3): 1194-200. Abstract: It is plausible to assume that exercise training, when applied early enough, can completely correct atherosclerotic defects. Using rabbit aortic specimens, we examined the effects of chronic exercise and high-cholesterol diet feeding on vascular function for different time periods. Male New Zealand White rabbits were divided into four groups: the normal diet groups with or without exercise training and the high-cholesterol diet groups with or without exercise training. Animals in high-cholesterol diet groups were fed 2% cholesterol rabbit chow for 2, 4, or 6 wk. Those in exercise training groups ran on a treadmill at 0.88 km/h for up to 40 min/day, 5 days/wk for the same period of time as the diet feeding. Thoracic aortas were isolated for functional and immunohistochemical analyses. We found that 1). although high-cholesterol diet feeding (>or=2 wk) elevated serum cholesterol levels and impaired acetylcholine-evoked vasorelaxation, only the latter effect was reversed by exercise training; 2). the effects of diet and exercise on acetylcholine-evoked vasorelaxation were mainly due to altered release of nitric oxide and endothelium-derived hyperpolarizing factor; and 3). diet feeding for 4 or 6 wk caused significant lipid deposition and expression of P-selectin, VCAM-1, monocyte chemoattractant protein-1, and inducible nitric oxide synthase, which were largely reduced by exercise training. In conclusion, parallel exercise training almost completely reverses the early-stage endothelial dysfunction caused by high-cholesterol diet feeding. |
| Effects of high-cholesterol diet on the interendothelial clefts and the associated junctional complexes in rat aorta Lee, W. C., W. T. Chao, et al. (2001), Atherosclerosis 155(2): 307-12. Abstract: The arterial endothelial intercellular cleft (AEC) and its associated junctional complex (JC) are the determinants of permeability to macromolecules. This study analyzed frequencies of AEC and JC profile types in the rat thoracic aorta at 1 and 12 months after feeding the animals with a normal or a high-cholesterol diet. Rats on either a normal diet or high-cholesterol diet for 12 months showed more of the simple 'end to end' or 'overlap' types (P < 0.01) but fewer complex 'interdigitating' type (P < 0.01) of AEC compared to the 1 month group. With regard to JC, the frequencies of gap junctions were decreased (P < 0.01) while the tight junctions and the normal junctionless complex were increased (P < 0.01) after 12 months of normal diet as compared with 1 month on the normal diet. These changes in frequencies for gap junction and tight junction were even greater for the high-cholesterol diet than for the normal diet treatment. Moreover, the incidence of open junctions was also noticeably increased after 12 months of high-cholesterol diet. These findings suggest that the proportions of the AEC and JC were highly responsive to aging whereas those of JC were more susceptible to the high-cholesterol diet treatment. |
| Effects of high-density lipoprotein particles containing apo A-I, with or without apo A-II, on intracellular cholesterol efflux Oikawa, S., A. J. Mendez, et al. (1993), Biochim Biophys Acta 1165(3): 327-34. Abstract: Previous reports have shown a differential effect of high-density lipoprotein (HDL) particles which contain apolipoprotein (apo) A-I without apo A-II (Lp A-I) and particles containing both apo A-I and apo A-II (Lp A-I/A-II) on cholesterol efflux from the mouse adipocyte cell line Ob1771, with Lp A-I and Lp A-I/A-II being active and inactive cholesterol efflux promotors, respectively. The present study was conducted to examine the roles of these two populations of apo-specific HDL particles on reverse cholesterol transport from cholesterol-loaded human skin fibroblasts and bovine aortic endothelial cells. The ability of HDL particles to remove intracellular cholesterol was tested by measuring depletion of the substrate pool for acylCoA:cholesterol acyltransferase (ACAT) and efflux of newly synthesized cholesterol, while removal of plasma membrane cholesterol was assessed by measuring efflux of 3Hcholesterol from prelabeled cells. Lp A-I and Lp A-I/A-II isolated from HDL2, HDL3 or plasma by immunoaffinity techniques each decreased esterification of cholesterol by both fibroblasts and endothelial cells. A mixture of Lp A-I and Lp A-I/A-II isolated from HDL3 decreased cholesterol esterification by fibroblasts in an additive manner, thus demonstrating that Lp A-I/A-II did not inhibit Lp A-I-mediated cholesterol efflux. Both Lp A-I and Lp A-I/A-II promoted efflux of sterol newly synthesized by fibroblasts, and no significant differences were observed between the apo-specific particles. Apo-specific particles were also similarly effective at preventing the accumulation of LDL-derived cholesterol in cholesterol-depleted fibroblasts. Efflux of 3Hcholesterol from plasma membranes was stimulated to similar extents by Lp A-I and Lp A-I/A-II isolated from either HDL2, HDL3 or plasma. Thus, the apo-specific HDL particles Lp A-I and Lp A-I/A-II are both effective promoters of cholesterol efflux from fibroblasts and aortic endothelial cells. |
| Effects of high-density lipoprotein(2) on cholesterol transport and acyl-coenzyme A:cholesterol acyltransferase activity in P388D1 macrophages Li, L. and H. J. Pownall (2001), Biochim Biophys Acta 1530(1): 111-22. Abstract: High-density lipoproteins are the putative vehicles for cholesterol removal from monocyte-derived macrophages, which are an important cell type in all stages of atherosclerosis. The role of HDL(2), an HDL subclass that accounts for most variation in plasma HDL-cholesterol concentration, in cholesterol metabolism in monocyte-derived macrophages is not known. In this study, the dose-dependent effects of HDL(2) on cellular cholesterol mass, efflux, and esterification, and on cellular cholesteryl ester (CE) hydrolysis using the mouse macrophage P388D1 cell line was investigated. HDL(2) at low concentrations (40 microg protein/ml) decreased CE content without affecting cellular free cholesterol content (FC), CE hydrolysis, or cholesterol biosynthesis. In addition, HDL(2) at low concentrations reduced cellular acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity and increased FC efflux from macrophages. Thus, HDL(2) has two potential roles in reverse cholesterol transport. In one, HDL(2) is an acceptor of macrophage FC. In the other, more novel role, HDL(2) increases the availability of macrophage FC through the inhibition of ACAT. Elucidation of the mechanism by which HDL(2) inhibits ACAT could identify new therapeutic targets that enhance the transfer of cholesterol from macrophages to the liver. |
| Effects of high-fat, low-cholesterol diets on hepatic lipid peroxidation and antioxidants in apolipoprotein E-deficient mice Ferre, N., J. Camps, et al. (2001), Mol Cell Biochem 218(1-2): 165-9. Abstract: The present study describes the effects of several high-fat low-cholesterol antiatherogenic diets on the hepatic lipid peroxidation and hepatic antioxidant systems in apolipoprotein E-deficient mice. Eighty mice were distributed into five groups and fed with regular mouse chow or chow supplemented with coconut, palm, olive and sunflower seed oils. After ten weeks, they were sacrificed and the livers were removed so that lipid peroxidation and alpha-tocopherol concentrations, and superoxide dismutase, glutathione peroxidase and glutathione reductase activities could be measured. The size of the atherosclerotic lesions in the aortas was also measured. Results showed that the diets supplemented with olive oil, palm oil or sunflower seed oil significantly decreased the size of the lesion. However, there was an association between those mice that were on diets supplemented with palm or coconut oils and a significant increase in hepatic lipid peroxidation. This association was not found in animals fed with olive or sunflower seed oils, the diets with the highest content of vitamin E. The dietary content of vitamin E was significantly correlated (r = 0.98; p < 0.05) with the hepatic concentration of this compound. Our study suggests that the high content of vitamin E in olive oil or sunflower seed oil may protect from the undesirable hepatotoxic effects of high-fat diets in apo E-deficient mice and that this should be taken into account when these diets are used to prevent atherosclerosis. |
| Effects of highly hydrogenated soybean oil and cholesterol on plasma, liver cholesterol, and fecal steroids in rats Kamei, M., S. Ohgaki, et al. (1995), Lipids 30(6): 533-9. Abstract: We investigated the relationship between dietary highly hydrogenated soybean oil (HSO) and cholesterol transport in rats. In the first study, to examine the effects on cholesterol transport of different concentrations of HSO in dietary oil, rats were given one of the three diets containing 0, 25, or 50% HSO in dietary oil with cholesterol (5 g/kg diet) or a diet without HSO and cholesterol for 22 d. Feeding the high concentration of HSO prevented the increase in plasma total cholesterol, hepatic total lipids, and cholesterol and the decrease in high-density lipoprotein-cholesterol, which were caused by dietary cholesterol. Moreover, HSO increased the fecal excretion, fecal lipids, and steroids in a dose-dependent manner. In the second study, to examine the effects on cholesterol transport of redistribution of steric acid in the triacylglycerol species contained in HSO, rats were given one of the six diets containing HSO (distearoylmonoacylglycerol and tristearoylglycerol)-rich, monostearoylglycerol-rich, or palmitic acid-rich oil with/without cholesterol (5 g/kg diet), for 30 d. Whereas the accumulation of cholesterol in the body was reduced, cholesterol excretion was enhanced effectively in rats given the HSO-rich diet compared with rats given the monostearoylglycerol-rich diet. These results suggested that not only the high concentration of stearic acid but also its uneven distribution in HSO-triacylglycerol contributed to the reduction in intestinal cholesterol absorption in rats. |
| Effects of HL-004, a novel ACAT inhibitor, on cholesterol accumulation and removal in cultured smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSP) Murakami, S., H. Araki, et al. (1995), Life Sci 56(7): 509-20. Abstract: The cholesterol metabolism of cultured smooth muscle cells (SMC) from the thoracic aorta of SMC from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) was compared. SMC from SHRSP had a higher acylCoA:cholesterol acyltransferase (ACAT) activity and accumulated more cholesterol than those from WKY. By using SMC from SHRSP, the effects of a novel ACAT inhibitor, HL-004, on the accumulation and removal of cholesterol were investigated. HL-004 inhibited microsomal ACAT activity from rabbit liver, intestine, aorta, and cultured SMC of SHRSP with 50% inhibition (IC50) values of 2.2, 1.7, 7.9, and 20 nM, respectively. HL-004 suppressed the accumulation of the intracellular cholesteryl ester (CE), but did not affect the intracellular free cholesterol (FC) content. Removal of cholesterol from the lipid-loaded SMC was accelerated by HL-004. These effects of HL-004 on cholesterol levels showed a good parallel to ACAT inhibition. It would thus appear that the suppression of cholesterol accumulation and the removal of cholesterol in SMC by HL-004 can be attributed to its ACAT inhibition in the cell, which reduces the content of intracellular CE. |
| Effects of HMG-CoA reductase inhibition on erythrocyte membrane cholesterol and acyl chain composition Dwight, J. F., A. C. Mendes Ribeiro, et al. (1996), Clin Chim Acta 256(1): 53-63. Abstract: The effects of 2 months treatment with simvastatin (40 mg, 20 mg p.o. daily) or placebo on erythrocyte membrane cholesterol content and acyl chain composition have been studied in 36 patients with a clinical history of atherosclerosis enrolled in the Oxford Cholesterol Study. All patients received advice corresponding to a standard phase 1 cholesterol-lowering diet. As expected the mean serum total cholesterol fell substantially (-26.5%, 20 mg simvastatin, P < 0.05; -32.7%, 40 mg simvastatin, P < 0.05) compared to placebo (-6.3%, ns). However, mean erythrocyte cholesterol content did not change significantly in any group (2 months therapy: 20 mg simvastatin, -0.62%; 40 mg simvastatin, +2.2%; placebo, -4.2%). Erythrocyte cholesterol was also unaltered after 5 months of therapy. Erythrocyte osmotic fragility was unchanged in the treatment and placebo groups. In the placebo group dietary advice alone was associated with a significant increase in the linoleic acid content of erythrocytes from 9.4 mole% of total acyl chains to 11.8 mole% (P < 0.05). Treatment with simvastatin was associated with an increase in the arachidonic acid content of the erythrocyte membrane from 12.2 to 15.3 mole% (P < 0.05). Treatment with simvastatin does not alter erythrocyte cholesterol content, but does alter acyl chain distribution. These results suggest that the chemical potential of cholesterol in serum is not markedly altered by HMG-CoA reductase inhibition. |
| Effects of HMG-CoA reductase inhibition on hepatic expression of key cholesterol-regulatory enzymes and receptors in nephrotic syndrome Vaziri, N. D. and K. Liang (2004), Am J Nephrol 24(6): 606-13. Abstract: BACKGROUND: Hypercholesterolemia is one of the major manifestations of nephrotic syndrome. We have previously shown that nephrotic hypercholesterolemia is associated with and, in part, due to dysregulation of hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7alpha-hydroxylase, as well as lecithin:cholesterol acyltransferase (LCAT), low-density lipoprotein (LDL) receptor and high-density lipoprotein (HDL) receptor deficiencies. This study was carried out to discern the effect of inhibition of HMG-CoA reductase on expression of the key enzymes and receptors involved in cholesterol metabolism in the liver. METHODS: Rats with puromycin-induced nephrotic syndrome were treated with either a statin (rosuvastatin 20 mg/kg/day) or placebo for 2 weeks. Placebo-treated normal rats served as controls. Gene expression, protein abundance and/or activities of relevant receptors and enzymes were quantified. RESULTS: The untreated nephrotic rats showed heavy proteinuria, hypoalbuminemia, hypercholesterolemia, elevated total cholesterol:HDL cholesterol ratio and normal creatinine clearance. This was associated with severe reductions in hepatic LDL receptor, hepatic HDL receptor and plasma LCAT concentration, marked upregulation of hepatic ACAT, and unchanged cholesterol 7alpha-hydroxylase (rate-limiting step in cholesterol catabolism). Statin administration for 2 weeks ameliorated hepatic LDL receptor and HDL receptor deficiencies and significantly lowered plasma cholesterol, LDL cholesterol, total cholesterol:HDL cholesterol ratio and proteinuria. CONCLUSIONS: HMG-CoA reductase inhibition improved hepatic LDL and HDL receptor deficiencies, and ameliorated the associated hyperlipidemia in the nephrotic rats. |