| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
| First Page | Previous Page | Next Page | Last Page |
| The genetic background of cholesterol gallstone formation: an inventory of human lithogenic genes Lammert, F. and S. Matern (2005), Curr Drug Targets Immune Endocr Metabol Disord 5(2): 163-70. Abstract: Family and twin studies as well as animal studies indicate that gallstone disease is, in part, genetically determined. Recently new single gene defects have been identified in specific patients with cholesterol and pigment gallstones. Examples include low phospholipid-associated cholelithiasis due to mutations of the gene encoding the hepatocanalicular phosphatidylcholine transporter, and pigment stones in association with mutations of the ileal bile salt transporter gene. Here we summarize the evidence for common genetic determinants of human gallstone disease in general and provide an inventory of human lithogenic genes. The precise understanding of such genes and their molecular mechanisms will establish new targets for rational drugdesign for this exceptionally prevalent and economically significant digestive disease. |
| The genetic determinants of plasma cholesterol and response to diet Humphries, S. E., R. E. Peacock, et al. (1995), Baillieres Clin Endocrinol Metab 9(4): 797-823. Abstract: In general, risk factors for multifactorial disorders such as atherosclerosis and hyperlipidaemia show a continuous distribution in the population, and this is the result of both interaction between genetic variation at genetic loci, and genetic and environmental interaction. Therefore, the investigation of the genetics of intermediate phenotypes such as levels of plasma lipid traits is likely to be particularly informative. Once the genes involved in determining the levels of these phenotypes have been identified, it should be possible to use the information to obtain a better understanding of the way these genetic variations determine the clinical end points. In the population it will be possible to identify a number of polygenes that are having a small effect on determining the trait, but for a particular individual, or the relatives of that individual, only a subset of all these polygenes will determine the level of the trait and therefore the risk of developing the disorder. In general, mutations with a large effect on the trait are rare in the population, By contrast, polymorphisms with a small effect on the trait may be common, such as is found with the effect of the apoE alleles and variation at the apoB gene locus on lipid levels. In the field of hyperlipidaemia and atherosclerosis research, molecular techniques have already given a great deal of information on how specific sequence variations in some of the candidate genes are involved in determining levels of plasma apoproteins, lipoproteins and lipids. As more mutations and sequence variations are identified, this will not only aid our understanding of the underlying pathology, but should be useful for identifying individuals who are at risk of developing atherosclerosis because of their particular genotype or combination of genotypes. |
| The Gordon Wilson Lecture. Plasma cholesterol: atherogenesis and mortality Fisher, W. R. (1992), Trans Am Clin Climatol Assoc 104: 77-92; discussion 92-3. |
| The great god cholesterol Holtzman, N. A. (1991), Pediatrics 87(6): 943-5. |
| The heart in Tangier disease. Severe coronary atherosclerosis with near absence of high-density lipoprotein cholesterol Mautner, S. L., J. A. Sanchez, et al. (1992), Am J Clin Pathol 98(2): 191-8. Abstract: Cardiac necropsy findings are described in a 72-year-old man with Tangier disease whose plasma total cholesterol levels averaged 70 mg/dL, low-density lipoprotein cholesterol level was 45 mg/dL, and high-density lipoprotein cholesterol level was 1.4 mg/dL, and who had coronary artery bypass grafting for severe atherosclerotic coronary artery disease. At necropsy, 24 of the 72 (33%) 5-mm segments of the 4 major (right, left main, left anterior descending, and left circumflex) native coronary arteries and 4 of the 27 (15%) 5-mm segments of the saphenous vein aortocoronary bypass conduits were narrowed by more than 75% in cross-sectional area by atherosclerotic plaques. The plaques were composed primarily (91% to 97%) of fibrous tissue. Oil red O staining, polarized light microscopy, and electron microscopy revealed cholesterol deposits in the plaques and in the walls of coronary arteries, saphenous vein grafts, and aorta. Such deposits also were found in foam cells of histiocytic origin, fibroblasts in all four cardiac valves, and in Schwann cells of cardiac nerves. |
| The heart of the matter. National guidelines urge more aggressive cholesterol treatment Leake, N. B. (2002), Adv Nurse Pract 10(1): 42-7; quiz 48-9. |
| The HELP-LDL-apheresis multicentre study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease. I. Evaluation of safety and cholesterol-lowering effects during the first 12 months. HELP Study Group Seidel, D., V. W. Armstrong, et al. (1991), Eur J Clin Invest 21(4): 375-83. Abstract: Fifty-one patients with coronary heart disease (CHD) and LDL-cholesterol levels greater than or equal to 200 mg dl-1 despite diet and drug therapy have been recruited into an angiographically controlled, multicentre, two-year study to evaluate HELP-LDL-apheresis in the secondary prevention of CHD. There were five drop-outs in the first year and 46 patients completed one year of therapy. An average of 2.791 of plasma was treated per patient every 7.7 days. Treatment was well tolerated and the incidence of side effects was small (2.9% of treatments). Mean pre-/post-apheresis LDL-cholesterol levels decreased from 283/120 mg dl-1 at baseline to 207/78 mg dl-1 and 203/76 mg dl-1 after 6 and 12 months, respectively. Mean pre-/post-apheresis HDL-cholesterol levels rose significantly over the course of therapy from 40.5/36.6 mg dl-1 to 44.8/39.7 mg dl-1 and 48.2/41.3 mg dl-1 after 0, 6 and 12 months, respectively. No major derangement of pre-apheresis haemostasis nor of haematological or clinical chemical parameters had occurred after 12 months of treatment. The data from this study support the feasibility of HELP-LDL-apheresis as an adjunctive therapy for lowering cholesterol levels in CHD patients refractory to cholesterol-lowering drugs while substantially improving the HDL/LDL ratio. |
| The HELP-LDL-apheresis multicentre study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease. II. Final evaluation of the effect of regular treatment on LDL-cholesterol plasma concentrations and the course of coronary heart disease. The HELP-Study Group. Heparin-induced extra-corporeal LDL-precipitation Schuff-Werner, P., H. Gohlke, et al. (1994), Eur J Clin Invest 24(11): 724-32. Abstract: The efficacy of the heparin-induced extracorporeal LDL-precipitation (HELP)-apheresis procedure has been studied in an open prospective multicentre trial. After 2 years of regular weekly HELP-treatment the data from 39 of 51 patients could be evaluated according to the study criteria. Twelve of the initially recruited study patients were omitted from the evaluation either because of premature termination of the treatment or because they did not fulfil the exact guidelines of the study protocol. A mean of 2.831 plasma was regularly treated on average every 7.85 days. The mean pre-/post-apheresis LDL-cholesterol levels decreased from 286/121 mg dl-1 at the first HELP treatment to 203/77 mg dl-1 after 1 year and to 205/77 mg dl-1 after 2 years of regular apheresis; the corresponding values for fibrinogen were 314/144, 246/98 and 250/105 mg dl-1, respectively. In contrast, the mean pre-/post-apheresis HDL-cholesterol levels rose from 41/38 through 51/44 mg dl-1 after 1 year to 52/43 mg dl-1 after 2 years of treatment. The overall result was a normalization of the atherogenic index (LDL-/HDL-cholesterol ratio) from 6.9/3.2 to 4.0/1.9. The angiographies from 33 patients obtained before and after 2 years of regular treatment could be evaluated blindly using the cardiovascular angiography analysis system. The mean degree of stenosis of all segments decreased from 32.5% (SD = 16) to 30.6% (SD = 16.8) over the 2 years. A regression > 8% was observed in 50/187 (26.7%) segments, whereas 29/187 (15.5%) segments showed progression. In 108/187 (57.8%) segments the lesions were stable (< 8% deviation) over 2 years. We conclude that regular treatment with HELP-LDL-apheresis is able to stabilize progressive atherosclerotic disease and to induce almost twice as much regression as progression of atherosclerotic lesions. |
| The high density lipoprotein- and apolipoprotein A-I-induced mobilization of cellular cholesterol is impaired in fibroblasts from Tangier disease subjects Walter, M., U. Gerdes, et al. (1994), Biochem Biophys Res Commun 205(1): 850-6. Abstract: Tangier disease (also known as familial HDL-deficiency) is characterized by very low high density lipoprotein (HDL) plasma levels, splenomegaly, and massive cholesteryl ester accumulation in the cytoplasm of various cell types. Since this phenotype may in part be caused by a defect in the pathway mediating cholesterol efflux from peripheral cells, we investigated the HDL3-mediated mobilization of cholesterol synthesized de novo from 14C-mevalonolactone in cultivated fibroblasts from two patients with Tangier disease. Our results indicate that the HDL3-induced translocation of 14C-cholesterol from intracellular pools to the plasma membrane and its subsequent secretion into the extracellular medium was approximately 50% less in the cells from the patients than in controls. The same result was also obtained with artificial apolipoprotein A-I-containing phospholipid vesicles. By contrast, no significant difference in HDL3-induced cholesterol efflux was observed when plasma membrane was labeled with exogenous 14C-cholesterol. We conclude that inefficient cholesterol efflux in Tangier disease is primarily caused by impaired HDL3-induced activation of cholesterol translocation from intracellular pools to the plasma membrane. |
| The highs and lows of talking to patients about cholesterol. TMA Communications and Public Service Committee Bowers, R. (1993), J Tenn Med Assoc 86(8): 357. |
| The human breast carcinoma cell line HBL-100 acquires exogenous cholesterol from high-density lipoprotein via CLA-1 (CD-36 and LIMPII analogous 1)-mediated selective cholesteryl ester uptake Pussinen, P. J., B. Karten, et al. (2000), Biochem J 349(Pt 2): 559-66. Abstract: Aberrant cell proliferation is one of the hallmarks of carcinogenesis, and cholesterol is thought to play an important role during cell proliferation and cancer progression. In the present study we examined the pathways that could contribute to enhanced proliferation rates of HBL-100 cells in the presence of apolipoprotein E-depleted high-density lipoprotein subclass 3 (HDL(3)). When HBL-100 cells were cultivated in the presence of HDL(3) (up to 200 microg/ml HDL(3) protein), the growth rates and cellular cholesterol content were directly related to the concentrations of HDL(3) in the culture medium. In principle, two pathways can contribute to cholesterol/cholesteryl ester (CE) uptake from HDL(3), (i) holoparticle- and (ii) scavenger-receptor BI (SR-BI)-mediated selective uptake of HDL(3)-associated CEs. Northern- and Western-blot analyses revealed the expression of CLA-1 (CD-36 and LIMPII analogous 1), the human homologue of the rodent HDL receptor SR-BI. In line with CLA-1 expression, selective uptake of HDL(3)-CEs exceeded HDL(3)-holoparticle uptake between 12- and 58-fold. Competition experiments demonstrated that CLA-1 ligands (oxidized HDL, oxidized and acetylated low-density lipoprotein and phosphatidylserine) inhibited selective HDL(3)-CE uptake. In line with the ligand-binding specificity of CLA-1, phosphatidylcholine did not compete for selective HDL(3)-CE uptake. Selective uptake was regulated by the availability of exogenous cholesterol and PMA, but not by adrenocorticotropic hormone. HPLC analysis revealed that a substantial part of HDL(3)-CE, which was taken up selectively, was subjected to intracellular hydrolysis. A potential candidate facilitating extralysosomal hydrolysis of HDL(3)-CE is hormone-sensitive lipase, an enzyme which was identified in HBL-100 cells by Western blots. Our findings demonstrate that HBL-100 cells are able to acquire HDL-CEs via selective uptake. Subsequent partial hydrolysis by hormone-sensitive lipase could provide 'free' cholesterol that is available for the synthesis of cellular membranes during proliferation of cancer cells. |
| The human cholesteryl ester transfer protein I405V polymorphism is associated with plasma cholesterol concentration and its reduction by dietary phytosterol esters Lottenberg, A. M., V. S. Nunes, et al. (2003), J Nutr 133(6): 1800-5. Abstract: We examined the relationships of I405V cholesteryl ester transfer protein (CETP), Taq1B CETP and apolipoprotein (apo)E polymorphisms with the pattern of response to dietary plant sterol ester (PSE) by plasma lipids and CETP concentrations as well as lecithin-cholesterol acyltransferase (LCAT) activity. Subjects with moderate primary hypercholesterolemia (20-60 y old; 50 women; 10 men) consumed margarine (20 g/d) without (placebo) or with PSE (2.8 g/d = 1.68 g/d phytosterols) for 4 wk each period, in a crossover, double-blind study. Plasma CETP concentration was measured by ELISA; endogenous LCAT activity was expressed as the percentage of esterification (30 min incubation) of the subjects' (14)C-unesterified cholesterol HDL. PSE reduced concentrations of plasma total cholesterol (TC) (10%) and LDL cholesterol (LDL-C) (12%). In relation to the I405V CETP polymorphism, the percentage reductions in TC with consumption of PSE for the II, IV and VV phenotypes were 7.2, 4.2 and not significant, respectively, whereas LDL-C significant reductions occurred only for II (9.5%). However, the CETP concentration diminished only in the II phenotype. |
| The human gallbladder increases cholesterol solubility in bile by differential lipid absorption: a study using a new in vitro model of isolated intra-arterially perfused gallbladder Ginanni Corradini, S., C. Ripani, et al. (1998), Hepatology 28(2): 314-22. Abstract: In this study, we first developed and validated a new in vitro isolated, intra-arterially perfused, gallbladder model and then applied the method to investigate the absorption of biliary lipids by the gallbladder wall and the effect of this process on the composition of human bile. Oxygenated and glucose-added buffer was perfused through the cystic artery to maintain organ viability. A standard pooled natural bile, radiolabeled with H3-cholesterol and C14-palmitoyl-linoleoyl-phosphatidylcholine, was instilled in the lumen via a cystic duct catheter. Changes in bile volume and lipid concentrations were monitored at time intervals to evaluate the disappearance of lipids from bile caused by gallbladder absorptive function. Organ viability was demonstrated by stable lactate dehydrogenase (LDH) organ release and oxygen consumption throughout the experiments. In the pig, disappearance rates of lipids from bile were similar in vitro and in vivo, demonstrating the validity of the isolated in vitro model for functional studies. By applying our in vitro isolated preparation to the human gallbladder, we found that 23% of cholesterol and 32% of phosphatidylcholine, but only 9% of bile salts, disappeared from bile in 5 hours. As a consequence, at the end of the experiments, cholesterol (P <.05) and phospholipid (P <.05) molar percentages were significantly reduced, while the bile salt (P <.05) molar percentage was significantly increased with respect to values at the beginning of the studies. Our findings are of pathophysiological relevance and support the concept that the human gallbladder modifies the relative composition of biliary lipids in such a way as to increase cholesterol solubility in bile. |
| The hydrophobic face orientation of apolipoprotein A-I amphipathic helix domain 143-164 regulates lecithin:cholesterol acyltransferase activation Sorci-Thomas, M. G., L. Curtiss, et al. (1998), J Biol Chem 273(19): 11776-82. Abstract: Apolipoprotein A-I (apoA-I) activates the plasma enzyme lecithin:cholesterol acyltransferase (LCAT), catalyzing the rapid conversion of lipoprotein cholesterol to cholesterol ester. Structural mutants of apoA-I have been used to study the details of apoA-I-LCAT-catalyzed cholesterol ester formation. Several studies have shown that the alpha-helical segments corresponding to amino acids 143-164 and 165-186 (repeats 6 and 7) are essential for LCAT activation. In the present studies, we examined how the orientation of the hydrophobic face, independent of an increase in overall hydrophobicity, affects LCAT activation. We designed, expressed, and characterized a mutant, reverse of 6 apoA-I (RO6 apoA-I), in which the primary amino acid sequence of repeat 6 (amino acids 143-164) was reversed from its normal orientation. This mutation rotates the hydrophobic face of repeat 6 approximately 80 degrees. Lipid-free RO6 apoA-I showed a marked stabilization when denatured by guanidine hydrochloride, but showed significant destabilization to guanidine hydrochloride denaturation in the lipid-bound state compared with wild-type apoA-I. Recombinant high density lipoprotein discs (rHDL) formed from RO6 apoA-I, sn-1-palmitoyl-sn-2-oleoyl phosphati-dylcholine, and cholesterol were approximately 12 A smaller than wild-type apoA-I rHDL. The reduced size suggests that one of the repeats did not effectively participate in phospholipid binding and organization. The sn-1-palmitoyl-sn-2-oleoyl phosphatidylcholine RO6 rHDL were a less effective substrate for LCAT. Mapping the entire lipid-free and lipid-bound RO6 apoA-I with a series of monoclonal antibodies revealed that both the lipid-free and lipid-bound RO6 apoA-I displayed altered or absent epitopes in domains within and adjacent to repeat 6. Together, these results suggest that the proper alignment and orientation of the hydrophobic face of repeat 6 is an important determinant for maintaining and stabilizing helix-bilayer and helix-helix interactions. |
| The hypercholesterolemic effect of dietary coconut fat versus corn oil in hypo- or hyperresponsive rabbits is not exerted through influencing cholesterol absorption Meijer, G. W., A. G. Lemmens, et al. (1991), Lipids 26(5): 340-4. Abstract: In two inbred strains of rabbits with high or low response of plasma cholesterol to dietary saturated versus polyunsaturated fatty acids, the efficiency of intestinal cholesterol absorption was measured. The feeding of a cholesterol-free purified diet containing saturated fatty acids in the form of coconut fat, when compared with a diet containing corn oil as polyunsaturated fatty acids, did not influence the efficiency of cholesterol absorption in the two rabbit strains. Irrespective of the dietary fat source, the hyperresponsive rabbits absorbed cholesterol more efficiently. It is concluded that the hypercholesterolemic effect of dietary coconut fat versus corn oil is not exerted by influencing cholesterol absorption. |
| The hypertension-lipid connection: insights into the relation between angiotensin II and cholesterol in atherogenesis Ferrario, C. M., R. Smith, et al. (2002), Am J Med Sci 323(1): 17-24. Abstract: Clinical data and experimental studies have established the important role of abnormal lipid metabolism in the causation of atherosclerosis and enthroned the hydroxymethylglutaryl coenzyme reductase inhibitors (statins) as a mainstay in management of patients with coronary heart disease. However, emerging experimental data underline the role of vascular renin-angiotensin systems in mediating the early stages of vascular endothelial dysfunction and inflammation as prerequisites for unleashing the cascade of cellular and molecular events that lead to the deposition of foam cells and their eventual progression to the atherosclerotic plaque. We discuss here the biological effects of statins and angiotensin II in the evolution of atherogenesis, underscoring possible links between statins and angiotensin receptor blockers. From the assessment of the commonality of effects resulting from the nonlipidic actions of statins and angiotensin II on the process of atherogenesis, we develop the argument that dyslipidemia may influence the ability to control blood pressure in hypertensive subjects and hypothesize that the combined use of statins and blockers of the renin-angiotensin system may have an additive effect in the management of hypertensive subjects. |
| The hypocholesterolemic action of TA-7552 and its effects on cholesterol metabolism in the rat Takashima, K., T. Kohno, et al. (1994), Atherosclerosis 107(2): 247-57. Abstract: The hypocholesterolemic property of 1-(3,4-dimethoxyphenyl)-2,3- bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene (TA-7552) and its effects on cholesterol metabolism were investigated in the rat. TA-7552 incorporated into a hypercholesterolemic diet at a concentration of 0.2% and administered for 7 days reduced serum cholesterol by 72% and liver cholesterol by 90%, and its minimal effective dose was 0.01% in the diet. Its hypocholesterolemic effect was associated with an elevation of serum HDL-cholesterol. Inclusion of 0.1% TA-7552 in the normal laboratory chow accelerated fecal excretion of 14C derived from orally administered 4-14Ccholesterol or carbonyl-14Ctaurocholate. The net amounts of fecal neutral sterols and bile acids were markedly increased by the same treatment. Hepatic bile acid production and hepatic and intestinal cholesterol biosynthesis as measured by cholesterol 7 alpha-hydroxylase activity and 1-14Cacetate incorporation into tissue cholesterol, respectively, were both stimulated by the drug treatment. All these data indicate that this hypocholesterolemic agent inhibits intestinal absorption of both cholesterol and bile acids and compensatorily stimulates hepatic production of bile acids and cholesterol. |
| The hypocholesterolemic agent dichloroacetate increases egg cholesterol content of laying hens Beyer, R. S. and L. S. Jensen (1993), Poult Sci 72(6): 1063-9. Abstract: Experiments were conducted to determine whether a diet with added dichloroacetate (DCA), an inhibitor of cholesterol biosynthesis, would influence plasma and egg cholesterol concentrations when fed to laying hens. In the first experiment, 62-wk-old laying hens (10 hens per treatment) were fed a control diet containing 0, 350, 700, or 1,400 ppm DCA for an 8-wk period. Egg production and size, feed intake, weight gain, and plasma and egg cholesterol were determined at biweekly intervals. In a second experiment, 36-wk-old laying hens (eight hens per treatment) received diets with 0, 3,000, or 6,000 ppm added DCA for a period of 6 wk. Production parameters and cholesterol measurements were conducted as in Experiment 1. Egg production and feed intake were significantly decreased with increasing levels of DCA in Experiment 1. In the second experiment, 6,000 ppm DCA sharply reduced feed intake, body weight, and egg production. Yolk weight and percentage yolk were significantly decreased by the higher levels of DCA used in Experiment 2. Total plasma cholesterol was not affected by dichloroacetate in either of the experiments. In contrast, egg cholesterol concentration increased by 10 and 37% in Experiments 1 and 2, respectively, in response to diets with added DCA when compared with the unsupplemented controls. Total egg cholesterol increased in response to dietary DCA in Experiment 1, but not consistently in Experiment 2 due to the decreased yolk size of the hens fed DCA. The results of these studies indicate that dietary DCA was not effective in reducing egg cholesterol concentrations. |
| The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP Janowski, B. A. (2002), Proc Natl Acad Sci U S A 99(20): 12675-80. Abstract: Oxysterols regulate cholesterol homeostasis through liver X receptor (LXR; cholesterol-lowering)- and sterol regulatory element-binding protein (SREBP; cholesterol-raising)-mediated signaling pathways. Previously we reported that the hypocholesterolemic agent LY295427 (4alpha-allylcholestan-3alpha-ol) reverses oxysterol-mediated suppression of SREBP processing. We now report that LY295427 increases expression of insulin-induced gene-1 (INSIG-1) and restores SREBP processing in cells treated with oxysterols. In cells overexpressing the INSIG-1 gene, by contrast, SREBP processing is suppressed and oxysterol regulation is disrupted. SREBP processing is not restored by addition of LY295427, but is restored by increasing the levels of SREBP cleavage-activating protein (SCAP). These findings suggest that the INSIG-1 protein alters sterol balance by modulating SREBP processing jointly with SCAP. To test whether the action of oxysterols on SREBP processing is mediated through endogenous INSIG-1 protein, we used RNAi to lower the expression of the INSIG-1 gene, and found that reduced INSIG-1 protein levels caused the loss of SREBP regulation by oxysterols. We conclude that: (i) INSIG-1 gene expression is suppressed by oxysterols; (ii) LY295427 treatment counters the suppressive effects of oxysterols on SREBP processing, resulting in the expression of the INSIG-1 gene; and (iii) INSIG-1 gene expression affects SREBP processing. Taken together, these data suggest that INSIG-1 plays a critical role in regulating cholesterol concentrations in the cell. |
| The hypocholesterolemic effect of dietary soybean protein vs. casein in hamsters fed cholesterol-free or cholesterol-enriched semipurified diets Terpstra, A. H., J. C. Holmes, et al. (1991), J Nutr 121(7): 944-7. Abstract: Golden Syrian hamsters fed a cholesterol-free diet containing 25% casein had higher plasma total triglyceride and cholesterol levels and VLDL + LDL cholesterol levels than animals fed a 25% soybean protein diet. Hamsters fed the cholesterol-free casein diet also had higher HDL cholesterol levels than animals fed the soybean protein diet, but these differences were not statistically significant. Addition of cholesterol to the diets caused even greater mean differences between the animals fed different types of protein, but the increased inter-animal variability of response to the added cholesterol resulted in less statistically significant differences. Although less responsive than the nonhybrid Golden Syrian hamsters, hybrid F1B hamsters showed similar effects of dietary casein vs. soybean protein on plasma lipids. These results indicate that the hamster may be a useful model to examine the effect of different types of protein and the interaction with dietary cholesterol on various plasma lipids and lipoproteins. |