| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Partitioning of NaPi cotransporter in cholesterol-, sphingomyelin-, and glycosphingolipid-enriched membrane domains modulates NaPi protein diffusion, clustering, and activity Inoue, M., M. A. Digman, et al. (2004), J Biol Chem 279(47): 49160-71. Abstract: In dietary potassium deficiency there is a decrease in the transport activity of the type IIa sodium/phosphate cotransporter protein (NaPi) despite an increase in its apical membrane abundance. This novel posttranslational regulation of NaPi activity is mediated by the increased glycosphingolipid content of the potassium-deficient apical membrane. However, the mechanisms by which these lipids modulate NaPi activity have not been determined. We determined if in potassium deficiency NaPi is increasingly partitioned in cholesterol-, sphingomyelin-, and glycosphingolipid-enriched microdomains of the apical membrane and if the increased presence of NaPi in these microdomains modulates its activity. By using a detergent-free density gradient flotation technique, we found that 80% of the apical membrane NaPi partitions into the low density cholesterol-, sphingomyelin-, and GM1-enriched fractions characterized as "lipid raft" fractions. In potassium deficiency, a higher proportion of NaPi was localized in the lipid raft fractions. By combining fluorescence correlation spectroscopy and photon counting histogram methods for control and potassium-deficient apical membranes reconstituted into giant unilamellar vesicles, we showed a 2-fold decrease in lateral diffusion of NaPi protein and a greater than 2-fold increase in size of protein aggregates/clusters in potassium deficiency. Our results indicate that NaPi protein is localized in membrane microdomains, that in potassium deficiency a larger proportion of NaPi protein is present in these microdomains, and that NaPi lateral diffusion is slowed down and NaPi aggregation/clustering is increased in potassium deficiency, both of which could be associated with the decreased Na/Pi cotransport activity in potassium deficiency. |
| Passive cigarette smoking and reduced HDL cholesterol levels in children with high-risk lipid profiles Neufeld, E. J., M. Mietus-Snyder, et al. (1997), Circulation 96(5): 1403-7. Abstract: BACKGROUND: HDL cholesterol levels are known to be lower in smokers than in nonsmokers. Previous studies have demonstrated an association of decreased HDL cholesterol with passive smoking in children but have not adjusted for potential confounding factors. METHODS AND RESULTS: In a cross-sectional, pilot-scale study, we examined the relationship of HDL cholesterol levels to passive smoking in children and adolescents referred to a tertiary hyperlipidemia clinic. Eligibility criteria included (1) first visit to a lipid clinic, (2) LDL cholesterol >95th percentile for age or HDL cholesterol <5th percentile, (3) age between 2 and 18 years, and (4) absence of secondary causes of hyperlipidemia. Sociodemographic information, diet record, medical history, and fasting lipid profiles were obtained. Of 109 eligible patients, 103 (94%) were studied. Twenty-seven percent came from households with cigarette smokers. HDL cholesterol levels were 38.7+/-1.2 mg/dL (mean+/-SEM) in passive smokers versus 43.6+/-1.2 mg/dL in children without smoke exposure (P=.005). Smoking exposure was not significantly associated with other lipid values. The effect of smoking on HDL cholesterol was minimally affected by potential confounders. In multivariate regression adjusting for body mass index, age, sex, exercise, and dietary fat intake, passive smoking remained a significant risk factor for decreased HDL cholesterol (P=.012). CONCLUSIONS: Mean HDL cholesterol levels are lower in dyslipidemic children from households with smokers than in those without household smoke exposure. Passive smoking may worsen the risk profile for later atherosclerosis among high-risk young persons. |
| Passive smoking increases experimental atherosclerosis in cholesterol-fed rabbits Zhu, B. Q., Y. P. Sun, et al. (1993), J Am Coll Cardiol 21(1): 225-32. Abstract: OBJECTIVES. We evaluated the influence of passive smoking on experimental atherosclerosis in cholesterol-fed rabbits. BACKGROUND. Exposure to environmental tobacco smoke (ETS) has been epidemiologically linked to death from ischemic heart disease in nonsmokers. METHODS. New Zealand male rabbits were randomly divided into three groups after 2 weeks of a 0.3% cholesterol diet. Sixteen rabbits were exposed to a high and 16 rabbits to a low dose of ETS; 32 rabbits located in another room served as an unexposed control group. After 10 weeks of ETS exposure, all rabbits were killed, and the percent of aortic and pulmonary artery endothelial surfaces covered by lipid lesions was measured by staining and planimetry. RESULTS. Average air nicotine, carbon monoxide and total particulate concentrations were 1,040 micrograms/m3, 60.2 ppm and 32.8 mg/m3 for the high dose ETS group, 30 micrograms/m3, 18.8 ppm and 4.0 mg/m3 for the low dose ETS group and < 1 microgram/m3, 3.1 ppm and 0.13 mg/m3 for the control group. The percent atherosclerotic involvement of the aorta and pulmonary artery increased significantly with ETS exposure (for the aorta, 30 +/- 19% mean +/- SD for the control group, 36 +/- 14% for the low dose ETS group and 52 +/- 21% for the high dose ETS group, p < 0.001; for the pulmonary artery, 22 +/- 15% for the control group, 29 +/- 25% for the low dose ETS group, and 45 +/- 12% for the high dose ETS group, p < 0.001). Bleeding time was significantly shorter in the two ETS groups than in the control group (86 +/- 17 vs. 68 +/- 15, 68 +/- 18 s, p < 0.001). There were no significant differences in serum triglycerides, cholesterol and high density lipoprotein cholesterol at the end of the study. CONCLUSIONS. Environmental tobacco smoke affects platelet function and increases aortic and pulmonary artery atherosclerosis. This increase of atherosclerosis was independent of changes in serum lipids and exhibited a dose-response relation. These results are consistent with data from epidemiologic studies demonstrating that ETS increases the risk of death due to heart disease. |
| Pathobiology of cholesterol gallstone disease: from equilibrium ternary phase diagram to agents preventing cholesterol crystallization and stone formation Portincasa, P., A. Moschetta, et al. (2003), Curr Drug Targets Immune Endocr Metabol Disord 3(1): 67-81. Abstract: The primum movens in cholesterol gallstone formation is hypersecretion of hepatic cholesterol, chronic surpersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles. Associated events include biochemical defects (increased biliary mucin, and increased proportions of hydrophobic bile salts in the intestine and gallbladder), motility defects (gallbladder smooth muscle hypocontractility in vitro and gallbladder stasis in vivo, sluggish intestinal transit), and an abnormal genetic background. The study of physical-chemical factors and pathways leading to cholesterol crystallization in bile has clinical relevance and the task can be carried out in different ways. The lithogenicity of bile is investigated in artificial model biles made by three biliary lipids - cholesterol, bile salts and phospholipids - variably combined in systems plotting within the equilibrium ternary phase diagram; also, crystallization propensity of ex vivo incubated human bile is studied by biochemical analysis of precipitated crystals, polarizing quantitative light microscopy and turbidimetric methods. The present review will focus on the recent advances in the field of pathobiology of cholesterol gallstones, by underscoring the role of early events like water transport, lipid transport, crystallization phenomena - including a genetic background - in gallstone pathogenesis. Agents delaying or preventing precipitation of cholesterol crystals and gallstone formation in bile will also be discussed. |
| Pathogenesis of atherosclerosis in patients with lipid metabolism disturbances: hypothesis on cholesterol utilization and atheromatous plaque formation Chepelenko, G. V. (2003), Angiol Sosud Khir 9(3): 20-5. Abstract: Cholesterol is known to participate in atheromatous plaque formation coming from blood stream and affecting vascular endothelium in environment of elevated low-density lipoproteins (LDL). Nevertheless, the occurrence of single atheromatous plaque evidences the possibility of local lipoprotein accumulation by vascular wall without systemic increase in serum LDLs. The author hypothesizes that in the absence of hypercholesterolemia atheroma can evolve through the utilization of modified LDL and free or etherified cholesterol, that remain in media non-removed by high density lipoproteins (HDL) owing to their structural damage after local vascular wall ischemia caused by vasa vasorum disorders. Disturbances in HDL acceptor function and transport of cholesterol and modified LDL to blood circulation and further into liver are followed by local accumulation of these products in smooth muscle cells. Overloaded by lipids smooth muscle cells move through internal fenestrated membrane thus activating receptor mechanism for transmission of modified lipoproteins to monocytes and capture of endothelial membrane and amorphous lipids by them in local lipid peroxidation area. A framework for hypothesis experimental and clinical testing is suggested. |
| Pathogenesis of cholesterol gallstones Strasberg, S. M., P. A. Clavien, et al. (1991), HPB Surg 3(2): 79-102. Abstract: Cholesterol gallstone disease is extremely common. Three major stages are recognized for stone formation, namely bile that becomes supersaturated with cholesterol, cholesterol nucleation leading to crystal formation and finally retention of the crystals in the gallbladder resulting in stone formation. Supersaturation is common but nucleation into crystals probably requires protein nucleating factors. Impaired motility of the gallbladder causes crystal retention and is probably very important in stone formation. |
| Pathogenesis of cholesterol gallstones: a parsimonious hypothesis Apstein, M. D. and M. C. Carey (1996), Eur J Clin Invest 26(5): 343-52. |
| Pathogenesis of orbital cholesterol granuloma Selva, D., S. E. Phipps, et al. (2003), Clin Experiment Ophthalmol 31(1): 78-82. Abstract: Two cases are presented of orbital cholesterol granuloma associated with gradual proptosis arising in men aged 35 and 41 years. Computed tomography demonstrated osteo-lytic masses in the frontal bone at the lacrimal fossa. Curettage revealed a characteristic histology of foreign body reactions surrounding cholesterol clefts. In both cases abnormal bone, more consistent with fibrous dysplasia than reactive change, was found at the periphery. The finding of abnormal bone associated with orbital cholesterol granulomas suggests that a pre-existing bone anomaly may be present in a subset of these cases. |
| Pathogenetic role of disorders of cholesterol metabolism in erythrocyte membranes in patients with exertion-induced angina pectoris Kokarev, A. N., I. Kardakov Iu, et al. (1991), Kardiologiia 31(2): 45-7. Abstract: A total of 90 working-age patients suffering from exercise-induced angina were examined. As the disease progressed, there was an inhibition of cholesterol esterification processes and an accumulation of dehydrocholesterol in the lipid bilayer of red blood cell membranes. The severity of coronary atherosclerosis evidenced by multi-position selective coronary angiography was found to show a significantly positive correlation with dehydrocholesterol levels and a negative correlation with the cholesterol/cholesterol ester ratio in the membranes of red blood cells. The use of finoptin in a daily dose of 320 mg in patients with exercise-induced angina diminished the magnitude of the potentially atherogenic alterations observed in cholesterol metabolism in the cell membranes. |
| Pathogenetic significance of cholesterol-containing immune complexes and lipid peroxidation in ischemic heart disease Urazgil'deeva, S. A., L. V. Shatalina, et al. (1999), Ter Arkh 71(12): 8-10. Abstract: AIM: To ascertain a relationship between cholesterol content in circulating immune complexes (CIC) and plasm lipid peroxidation (LPO) in patients with ischemic heart disease (IHD). MATERIALS AND METHODS: Blood samples from 33 IHD patients 23 of which had a history of myocardial infarction and from 8 healthy subjects were examined for total cholesterol, high and low density lipoproteins cholesterol, CIC, the ability of blood serum to induce free radicals, superoxide dismutase. RESULTS: A statistically significant positive correlation was found between CIC cholesterol level and content of free radicals while a negative correlation existed between superoxide dismutase activity and high density lipoprotein cholesterol level in blood plasm of healthy individuals and patients with IHD. After myocardial infarction an inversion of the above parameters was seen as a result of disorders in both antioxidant and immune systems. CONCLUSION: The level of both LPO and CIC cholesterol, their interaction are important atherogenic factors in development of IHD. |
| Pathogenic factors in early recurrence of cholesterol gallstones Berr, F., M. Mayer, et al. (1994), Gastroenterology 106(1): 215-24. Abstract: BACKGROUND/AIMS: Supersaturation of bile with cholesterol, rapid nucleation of cholesterol crystals, and/or incomplete emptying of the gallbladder are believed to be required for gallstone formation. The importance of these factors for the recurrence of gallbladder stones was studied. METHODS: Twenty patients, untreated after successful shock wave therapy, were studied in a matched case-control design for bile acid turnover, composition of duodenal bile, and gallbladder emptying. In 10 of them, gallstones had recurred within 12 +/- 2 months (X +/- SEM); the other 10 had been free of stones since 22 +/- 3 months. RESULTS: In each group, duodenal bile was supersaturated with cholesterol in 8 of 10 patients and showed abnormal nucleation time of cholesterol crystals in half of the patients. Patients with recurrent stones had smaller pool sizes of cholic acid (-43%) and enhanced conversion of cholic acid to deoxycholic acid. The odds for stone recurrence were ninefold increased in the presence of excessive deoxycholic acid (exceeding cholic acid) in the bile acid pool or incomplete emptying of the gallbladder (residual volume > 5 mL) in response to cholecystokinin. The odds ratio was over 20-fold increased when incomplete emptying of the gallbladder coincided with supersaturated bile or with excessive deoxycholic acid. CONCLUSIONS: Enhanced conversion of cholic acid to deoxycholic acid and incomplete emptying of the gallbladder could be important cofactors for the recurrence of gallstones. |
| Pathological case of the month. Cholesterol granuloma as a cause of fever of unknown origin Rothschild, M., I. Berger, et al. (1997), Arch Pediatr Adolesc Med 151(9): 951-2. |
| Pathological cholesterol metabolism fails to modify electrophysiological properties of afflicted neurones in Niemann-Pick disease type C Deisz, R. A., V. Meske, et al. (2005), Neuroscience 130(4): 867-73. Abstract: Niemann-Pick disease type C (NPC) is a recessive inherited neurovisceral lipid storage disease characterized by progressive motor impairment and a loss of neurones including those integrated into the motor system. One of the key neuropathological findings is the intracellular accumulation of lysosomes enriched with free cholesterol. This accumulation is due to impaired transport proteins named NPC1 (approx. 95% of the cases) or NPC2 (approx. 5%) responsible for the transport of endocytosed cholesterol from lysomes to plasma membranes. The perturbed lipid-transport in NPC cells leads to an altered lipid composition of the plasma membrane. Available evidence suggests that the lipid matrix influences the electrophysical properties of ion channels in membranes. We therefore evaluated whether electrophysiological properties of NPC neurones differ from healthy neurones. Both, acute brain slices and primary neuronal cell cultures from wildtype and NPC mice, a well-established mouse model for the Niemann-Pick type C disease, were used for a comparison of electrophysiological properties like resting membrane potential, input resistance, action potential amplitudes and synaptic properties of the neurones. In addition we optically recorded the changes of intraneuronal calcium levels elicited by depolarization. Our results show that the characteristics of ion channels in NPC neurones do not differ significantly from wildtype neurones. We therefore conclude that gross alterations of the electrophysiological properties of neurones will probably not initiate or substantially contribute to the development of the motor impairment or other neurological signs of NPC. |
| Pathology of atherosclerosis in cholesterol-fed, susceptible mice Stewart-Phillips, J. L. and J. Lough (1991), Atherosclerosis 90(2-3): 211-8. Abstract: In recent years the C57BL/6J mouse has gained popularity as a model for studying the genetics of diet-induced atherosclerosis. After 10-20 weeks of consuming a diet enriched with saturated fat and cholesterol, it develops fatty streak-like lesions in the valve sinus region of the ascending aorta. The current study shows that continuing the atherogenic diet for a further 15 weeks leads to the development of fibro-fatty lesions which have many of the characteristics of human atheromatous plaques. This finding lends credence to the use of C57BL/6J mice for studying the pathogenesis of atherosclerosis. |
| Pathophysiology and management of low high-density lipoprotein cholesterol Rader, D. J. (1999), Am J Cardiol 83(9B): 22F-24F. Abstract: Low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of coronary artery disease events. Data in animals indicate that increasing HDL cholesterol levels decreases progression of atherosclerosis. Some clinical trials suggest a benefit from increasing HDL cholesterol levels, but additional data in humans are needed. Nevertheless, in patients with, or at high risk for, coronary artery disease, a decision to institute drug therapy that includes an effort to increase HDL cholesterol levels is reasonable based on available data. Several clinical trials are underway to determine the most effective drug therapy for decreasing the risk of coronary artery disease associated with low HDL cholesterol levels. |
| Pathophysiology and pathogenesis of cholesterol gallstone formation Hay, D. W. and M. C. Carey (1990), Semin Liver Dis 10(3): 159-70. |
| Pathophysiology of cholesterol gallstone disease Mendez-Sanchez, N., R. Cardenas-Vazquez, et al. (1996), Arch Med Res 27(4): 433-41. Abstract: The purpose of the present paper is to review the current knowledge about cholesterol gallstone disease. It is generally accepted that the formation of cholesterol gallstone requires three major pathogenic defects, namely, supersaturation, nucleation and crystal growth as well as disorder of gallbladder motility. The supersaturation is necessary but not sufficient to explain stone formation. It has been suggested that nucleation is the key factor for gallstone formation. However, those three factors are necessary for the formation of cholesterol gallstones, and the presence of just one or two factors does not lead to stones. We also touch briefly on the results from studies performed in Mexico in this area. |
| Pathophysiology of elevated ascites fluid cholesterol in malignant ascites. Increased ascites to serum relation of proteins and lipoproteins in patients with peritoneal carcinomatosis as compared to patients with cirrhosis of the liver Jungst, D., Y. Xie, et al. (1992), J Hepatol 14(2-3): 244-8. Abstract: The existence of marked elevations of ascitic fluid cholesterol has been observed in patients with peritoneal carcinomatosis compared to patients with cirrhosis and has been found useful in differential diagnosis. This finding could be caused by an enhanced movement of plasma lipoproteins into the peritoneal cavity. To test this hypothesis we determined the fasting concentrations of total, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol, apolipoprotein-A1 (apo-A1) and apolipoprotein-B (apo-B) in serum and ascites of 17 patients with cirrhosis and 16 patients with peritoneal carcinomatosis. The movement of proteins from plasma to ascites was calculated from the ascites/serum concentration ratios of six different sized proteins with a molecular mass ranging from 54 kDa to 971 kDa. Mean values (mg/dl) for total cholesterol (92.6 vs. 21.0), HDL-cholesterol (15.6 vs. 1.8), LDL-cholesterol (63.4 vs. 16.1), apo-A1 (50.2 vs. 13.6) and apo-B (41.2 vs. 12.9) in ascites were significantly higher in peritoneal carcinomatosis than in cirrhosis. These differences could only partially be explained by the higher serum concentrations of these parameters in peritoneal carcinomatosis, but were mainly due to a lower selectivity for the movement of plasma proteins and lipoproteins into ascites (mean ascites/serum (A/S) ratio: 0.30-0.77) in peritoneal carcinomatosis as compared to cirrhosis (mean ascites/serum ratio: 0.11-0.21). In both groups about 85% of the total cholesterol in serum and ascites consisted of HDL- and LDL-cholesterol. These findings support the hypothesis that elevations in ascitic cholesterol in peritoneal carcinomatosis compared to cirrhosis are mainly caused by the increased movement of plasma HDL and LDL into the peritoneal cavity. |
| Pathway of cholesterol efflux from human hepatoma cells Sviridov, D. and N. Fidge (1995), Biochim Biophys Acta 1256(2): 210-20. Abstract: Studies have been carried out with HepG2 cells, as a model for human hepatocytes, to explore a novel proposition that the liver contributes free cholesterol to the plasma lipoproteins which participate in the process of reverse-cholesterol transport. Specifically, we compared efflux of cholesterol from HepG2 cells and human fibroblasts (a model for extrahepatic tissues) after labeling cells with 14Ccholesterol. Incubation of both types of cells with human serum resulted in the efflux of 14Ccholesterol and net cholesterol flux from the cells to the medium and its subsequent esterification. Rates of cholesterol efflux from HepG2 cells and fibroblasts were similar. Nondenaturing two-dimensional gel electrophoresis showed that about 10% of the cell-derived 14Ccholesterol moves rapidly through pre beta 1-. pre beta 3- and pre beta 2-HDL particles into alpha HDL and LDL, although the majority moves directly to alpha HDL and LDL, with most of 14Ccholesterol and cholesterol mass accumulating in LDL. When cells were incubated with equivalent concentrations of isolated lipoproteins, HDL was much more effective in promoting 14Ccholesterol efflux than LDL, suggesting that unesterified cholesterol is initially transferred to HDL and then to LDL. Incubation with whole serum in contrast to isolated lipoproteins did not enhance cholesterol efflux despite a 3-fold higher esterification rate. We also investigated the identity of newly secreted lipoproteins following the labeling of HepG2 cells with 14Ccholesterol: 72% of labeled cholesterol was released as LDL, 20% was released as pre beta 2-HDL and 8% as small alpha HDL particles. Novel apo A-I rich but 14Ccholesterol-deficient pre beta 1-HDL particles were also secreted by HepG2 cells. |
| Pathways of cholesterol crystallization in model bile and native bile Portincasa, P., A. Moschetta, et al. (2003), Dig Liver Dis 35(2): 118-26. Abstract: Hypersecretion of hepatic cholesterol, chronic supersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles represent the primum movens in cholesterol gallstone formation. Physical-chemical factors and pathways leading to cholesterol crystallization can be investigated in artificial model biles and ex vivo in fresh human bile. Depending on modulatory factors (i.e., lipid concentration, bile salt or phospholipid species, humidity, mucins, etc.), cholesterol can precipitate in several forms (i.e., monohydrate, anhydrous) and habits (i.e., plate-like, needle-like, intermediate arcs, filaments, tubules, spirals). Careful analysis of biliary cholesterol crystals includes biochemical analysis of precipitated crystals, polarizing quantitative light microscopy, and turbidimetric methods. In this paper, recent concepts on cholesterol crystallization in artificial model biles as well as in human bile will be reviewed. |