| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Intermediate density lipoprotein cholesterol as the best lipoprotein predictor of atherosclerosis severity in the Watanabe Heritable Hyperlipidemic rabbit Nordestgaard, B. G., B. Agerholm-Larsen, et al. (1997), Atherosclerosis 132(1): 119-22. |
| Intermembrane cholesterol transfer: role of sterol carrier proteins and phosphatidylserine Schroeder, F., P. Butko, et al. (1990), Lipids 25(11): 669-74. Abstract: The effect of phosphatidylserine and sterol carrier proteins on cholesterol exchange was determined using an assay not requiring separation of donor and acceptor membrane vesicles. Sterol carrier protein-2 (SCP2, also called nonspecific lipid transfer protein), but not fatty acid binding protein (FABP, also called sterol carrier protein), enhanced the initial rate of sterol exchange between neutral zwitterionic phosphatidylcholine small unilamellar vesicles (SUV) 2.3-fold. Phosphatidylserine at 10 mol% increased the initial rate of spontaneous and of SCP2-mediated (but not FABP-mediated) sterol exchange by 22% and 44-fold, respectively. The SCP2 potentiation of sterol transfer was dependent on SCP2 concentration and on phosphatidylserine concentration. The SCP2-mediated sterol transfer was inhibited by a variety of cations including KCl, divalent metal ions, and neomycin. The data suggest that SCP2 increase in activity for sterol transfer may be partly ascribed to charge on the phospholipid. |
| Internalized plasma membrane cholesterol passes through an endosome compartment that is distinct from the acid vesicle-lysosome compartment Porpaczy, Z., J. J. Tomasek, et al. (1997), Exp Cell Res 234(2): 217-24. Abstract: Cholesterol from the plasma membrane of MA-10 Leydig tumor cells is internalized into the cell and either esterified or used as substrate for steroid hormone synthesis. In the present studies we show that chloroquine and sphinganine cause LDL cholesterol and cholesteryl esters to accumulate in the cells. A lysosome fraction contained the excess cholesterol and cholesteryl esters. Both inhibitors blocked the conversion of plasma membrane cholesterol into intracellular cholesteryl esters and caused dose-dependent inhibition of dibutyryl-cAMP-stimulated progesterone synthesis. Radiolabeled cholesterol applied to the plasma membrane of MA-10 cells accumulated in the lysosome fraction of chloroquine and sphinganine-treated cells. Evidence that these inhibitors did not require the Golgi was provided by experiments using brefeldin A. Experiments utilizing a fluorescent cholesterol analogue and a lysosomal marker indicated that cholesterol entered the cells in structures that were different than the acidic vesicle-lysosome compartment. Consistent with this observation was the observation that the peak fluorescence fractions of cells subjected to density gradient centrifugation was of lower density than the lysosome fraction. |
| International comparisons of plasma cholesterol and lipoproteins Labarthe, D. R., B. O'Brien, et al. (1991), Ann N Y Acad Sci 623: 108-19. |
| International Congress of Biochemistry and Molecular Biology Satellite Conference: cellular cholesterol ester metabolism Erickson, S. K. (1998), J Lipid Res 39(11): 2300-3. |
| International quality assurance schemes for cholesterol Grafnetter, D. (1990), Scand J Clin Lab Invest Suppl 198: 32-42. Abstract: Lipid disorders rank high among the risk factors known to be associated with development of cardiovascular diseases which constitute a great socio-economic problem in many countries. Blood lipid lipoprotein and apolipoprotein measurements belong in all types of medical services to the most important ones not only because of their diagnostic but also of predictive value. Especially the measurement of blood cholesterol concentration is used in different studies and population screenings as an aid in establishing the degree of the risk of the development of cardiovascular disease. Accurate methods and uniform decision cut-points are needed for identifying individuals at high risk for comparability among results from different places and for preventing false diagnostic decisions based on inaccurate measurements. International Reference and/or Standardization Centres are of utmost importance helping to bring methods into uniform accuracy and precision limits everywhere. Local reference and standardization centres can be created with their assistance. Using the example of control of total cholesterol methods this paper describes some of the activities of the WHO Lipid Reference Centre at the Institute for Clinical and Experimental Medicine (IKEM) in Prague Czechoslovakia which shows comparability to the Centres for Disease Control (CDC Atlanta) standardization basis and mentions several other standardization centres in different countries. |
| International Symposium on Reverse Cholesterol Transport. Report on a meeting Lacko, A. G. and P. H. Pritchard (1990), J Lipid Res 31(12): 2295-9. Abstract: The purpose of this symposium was to provide a forum for the reporting of recent findings and the exchange of ideas concerning reverse cholesterol transport, an area of intense interest and some controversy. Data from epidemiological studies have consistently shown that elevated levels of high density lipoproteins (HDL) are an index of increased protection against coronary heart disease. However, the mechanism whereby HDL is involved in the prevention and/or reversal of atherosclerosis is unknown. According to one of the hypotheses, HDL acts as the primary acceptor of unesterified cholesterol from cells and functions jointly with the enzyme lecithin:cholesterol acyltransferase (LCAT) and the cholesteryl ester transfer protein (CETP) to facilitate the movement of cholesterol from peripheral tissues to the plasma and ultimately to the liver. Although this mechanism as originally proposed by Glomset is an essential physiological mechanism, the clinical significance of this hypothesis remains unsubstantiated. Key elements of knowledge are lacking that would allow the linking of cholesterol efflux from cells and tissues with specific events in HDL metabolism, particularly those that are relevant to the prevention and/or reversal of atherosclerosis. Because of the intricate nature of the interaction between the components of reverse cholesterol transport, a conference involving the leading investigators of the field, where extensive discussion of the findings and ideas is allowed, appeared highly desirable. Indeed, from the distance of nearly 4 months, feedback from the participants indicates that the meeting was highly successful and the organizers feel that all the projected goals of the symposium were accomplished. |
| Interrelationship between dietary protein, cholesterol and n-6 polyunsaturated fatty acid metabolism Huang, Y. S., K. Koba, et al. (1993), Prog Lipid Res 32(2): 123-37. |
| Interrelationship of dietary lipids and ascorbic acid with hepatic enzymes of cholesterol metabolic pathway Sen, S. and S. Mukherjee (1997), Indian J Exp Biol 35(1): 42-5. Abstract: Effect of unsaturated and saturated fats on cholesterol metabolism was studied in ascorbate sufficient and deficient guineapigs. Experimental animals were made chronic ascorbic acid deficient by allowing oral intake of 0.5 mg ascorbic acid/day/animal. Elevation in serum and liver cholesterol and triglyceride along with depression in cholesterol oxidation and 7 alpha-hydroxylation in liver was observed in unsaturated fat fed guineapigs with ascorbate deficiency. Liver microsomal cytochrome P-450 level was found to be low in ascorbate deficient animals. Polyunsaturated fat intake could not lower the serum cholesterol level in ascorbate deficiency. Today polyunsaturated fat in the diet is encouraged all over the world for its hypocholesterolemic effect. This study indicates that polyunsaturated fat intake with ascorbic acid deficiency may produce hypercholesterolemia. |
| Interrelationships of bile acid and phospholipid fatty acid species with cholesterol saturation of duodenal bile in health and gallstone disease Berr, F., E. Schreiber, et al. (1992), Hepatology 16(1): 71-81. Abstract: The relative amount of cholesterol and the fatty acid composition of phosphatidylcholines in bile can be influenced by the bile acid species secreted. To search for a contribution of secondary bile acids and of phosphatidylcholines to supersaturation of bile in gallstone disease, we compared the relative amount of cholesterol and the biliary composition of bile acids and of phospholipid fatty acids in cholecystokinin-stimulated duodenal bile of 22 female gallstone patients and 16 healthy controls and analyzed the interrelationships of these bile constituents. Gallstone patients had higher molar percentages of cholesterol than did controls (10.2 +/- 3.2 vs. 6 +/- 1.5 mol%; p less than 0.001) and demonstrated a trend toward larger fractions of deoxycholic and lithocholic acids. By linear models, variation of cholesterol saturation could be predicted (p less than 0.001) up to 53% by the bile acid pattern and up to 81% by the fatty acid pattern of phospholipids. Linear path analysis (goodness-of-fit index = 0.973) confirmed the tight relationship between phospholipid fatty acids (positive: oleic, arachidonic; negative: linoleic, palmitoleic) and the relative amount of cholesterol; more than half the influence of cholic, deoxycholic and lithocholic acids on the relative amount of cholesterol could be explained indirectly by their influence on the phospholipid fatty acid pattern. We conclude that the relationships examined by path analysis support the working hypothesis that secondary bile acids contribute to supersaturation of bile mainly by changing the fatty acid pattern of the secreted phospholipids (presumably the pattern of phosphatidylcholines), which increases the molar ratio of cholesterol/phospholipids in bile. |
| Inter-relationships of plasma fibrinogen, low-density lipoprotein cholesterol, cigarette smoking and the prevalence of cardiovascular disease Fowkes, F. G., A. J. Lee, et al. (1996), J Cardiovasc Risk 3(3): 307-11. Abstract: BACKGROUND: The magnitude of the cardiovascular risk associated with plasma fibrinogen concentration is influenced separately by cigarette smoking and by low-density lipoprotein (LDL) cholesterol levels. The effects of combinations of these factors on risk and the extent to which inclusion of the plasma fibrinogen level further refines the risks associated with smoking and high LDL cholesterol levels are not known. OBJECTIVE: To determine the inter-relationships among all of the three factors smoking, LDL cholesterol level and fibrinogen level with respect to the occurrence of cardiovascular disease. METHODS: The study was part of the Edinburgh Artery Study, which was a cross-sectional random sample survey of 1592 men and women aged 55-74 years. The assessment of cardiovascular disease included recall of diagnosis by a doctor of angina or myocardial infarction, intermittent claudication determined by a questionnaire and measurement of ankle systolic blood pressure. RESULTS: The odds ratio for disease in smokers in the top tertiles of plasma fibrinogen and LDL cholesterol levels was 7.7 (95% confidence interval 3.0-19.8; P < or = 0.001). Neither a multiplicative nor a synergistic effect of the three factors on the odds of disease was observed but the level of each contributed to the risk. For example, in current smokers in the bottom tertile of LDL cholesterol level, the odds of disease were 6.1 (95% confidence interval 2.2-17.0; P < or = 0.001) in the top tertile, 2.9 (95% confidence interval 1.0-8.6; P < or = 0.05) in the middle tertile and 1.6 (95% confidence interval 0.5-4.8; P > 0.05) in the bottom tertile of plasma fibrinogen level. Subjects in the bottom tertile of plasma fibrinogen level did not have significantly elevated (P < 0.05) risks irrespective of LDL cholesterol levels and smoking status. CONCLUSION: The incorporation of plasma fibrinogen level permitted more precise delineation of the odds of disease within categories of smoking and LDL cholesterol concentration. These relationships need to be investigated further in prospective studies. |
| Interruption of the enterohepatic circulation of bile acids stimulates the esterification rate of cholesterol in human liver Stahlberg, D., E. Reihner, et al. (1991), J Lipid Res 32(9): 1409-15. Abstract: The activity of acyl CoA: cholesterol acyltransferase (ACAT), which catalyzes the esterification of cholesterol, was studied in liver microsomes obtained from cholestyramine-treated gallstone patients (n = 12) and patients with Crohn's disease who had undergone partial ileal resection (n = 11). Gallstone patients (n = 33) and gallstone-free subjects undergoing cholecystectomy because of polyps of the gallbladder (n = 8) served as controls. The mean levels of the ACAT activity were the same in the gallstone and the gallstone-free patient groups (6.0 +/- 0.4 and 6.1 +/- 1.1 pmol/min per mg protein, respectively). When exogenous cholesterol was added to the assay system the activities were increased four- to fivefold in both groups. The ACAT activity tended to be increased in the cholestyramine-treated patients (8.1 +/- 1.8 pmol/min per mg protein), and was significantly enhanced (P less than 0.005) in the ileal-resected patients (12.3 +/- 2.3 pmol/min per mg protein). When the enzyme activity was determined with added exogenous cholesterol, it was significantly higher compared to the controls in both the cholestyramine-treated patients and the patients with ileal resection (57.9 +/- 11.6 and 50.0 +/- 10.3 pmol/min per mg protein, respectively). The content of free and esterified cholesterol in liver homogenates and microsomes was not significantly different between the patient groups. We conclude that ACAT activity is increased in patients with interruption of the enterohepatic circulation of bile acids, and speculate that this reflects a stimulated uptake of lipoprotein cholesterol and may indicate that more cholesteryl esters are incorporated into very low density lipoproteins. |
| Intestinal absorption and biliary secretion of cholesterol in rats with nephrotic syndrome Pahl, M. V., F. Oveisi, et al. (1998), Nephrol Dial Transplant 13(6): 1446-51. Abstract: BACKGROUND: Nephrotic syndrome (NS) results in hypercholesterolemia which is attributed to increased production and decreased removal of cholesterol-rich lipoproteins. Adjustments in intestinal absorption are reportedly involved in cholesterol homeostasis. We, therefore, studied the intestinal absorption and biliary excretion of cholesterol in NS. METHODS: We studied intestinal absorption (by in vivo perfusion and in vitro everted sac incubation techniques) and biliary secretion (by common bile duct cannulation) of cholesterol in rats with puromycin-induced NS. The results were compared with those obtained from pair-fed control (PF) animals, those given free access to food (NL) or those fed a hypercholerolemic diet (H-chol group). Micellar solutions of Krebs' phosphate buffer containing trace amounts of 14Cinulin and 3Hcholesterol, as well as different concentrations of unlabeled cholesterol, were used for absorption studies. RESULTS: The NS and H-chol groups showed severe and comparable hypercholesterolemia. No significant difference was found in the rate of biliary cholesterol secretion among the study groups. Likewise, the rates of in vivo and in vitro cholesterol absorptions in the NS and H-chol groups were comparable with one another and similar to those found in the NL and PF groups. The rate of in vitro cholesterol absorption was directly proportional to its concentration in the incubation media at low concentrations. However, the absorption rate showed a pattern consistent with saturable transport at high cholesterol concentrations in all groups. CONCLUSIONS: We conclude that intestinal absorption and biliary secretion of cholesterol are not appreciably influenced by either nephrotic or diet-induced hypercholesterolemia in rats. The data further suggest that cholesterol absorption may be a saturable process. |
| Intestinal absorption of cholesterol by patients with Smith-Lemli-Opitz syndrome Lin, D. S., R. D. Steiner, et al. (2005), Pediatr Res 57(6): 765-70. Abstract: The Smith-Lemli-Opitz syndrome (SLOS) is a disorder of impaired cholesterol biosynthesis because of a deficiency of the enzyme 7-dehydrocholesterol-Delta(7)-reductase, in the last step in cholesterol biosynthesis. Dietary cholesterol has been proposed as a potential therapy for SLOS and is being tested currently. Because there is no information on cholesterol absorption in SLOS, we recruited 12 SLOS patients into the General Clinical Research Center for 1-wk periods for administration of test meals and for blood and stool collections. A test breakfast that contained tracer cholesterol-4-C(14) with egg yolk or with crystalline cholesterol in suspension was given subsequently. Twenty-four and 48-h blood and 1-wk stool samples then were collected. The radioactivities in these samples were analyzed to determine the absorption of cholesterol by these patients. In 11 patients who were given egg yolk cholesterol, cholesterol absorption was 27.3 +/- 6.7%. The absorption was slightly less at 20.5 +/- 10.3% but not significantly different for the six patients who were given crystalline cholesterol. There was a positive correlation between the absorption of isotopic cholesterol as measured by determination of radioactive cholesterol in stool and the amount of isotopic cholesterol in the plasma at 24 and 48 h after the meal. Our data indicated that SLOS patients absorb cholesterol from the diet. However, the percentage of absorption is lower than reported values for normal adults and for hypercholesterolemic children. The absorption of crystalline cholesterol in suspension was slightly lower than the absorption of cholesterol in egg yolk cholesterol by these patients. The absorption of cholesterol may ameliorate some of the biochemical and developmental deficits in SLOS patients. |
| Intestinal absorption of cholesterol is mediated by a saturable, inhibitable transporter Hernandez, M., J. Montenegro, et al. (2000), Biochim Biophys Acta 1486(2-3): 232-42. Abstract: Although the mechanism by which dietary cholesterol is absorbed from the intestine is poorly understood, it is generally accepted that cholesterol is absorbed from bile acid micelles in the jejunum. Once inside the enterocytes, cholesterol is esterified by the action of acyl-coenzyme A:cholesterol acyltransferase (ACAT), assembled into chylomicrons, and secreted into the lymph. In this work, mechanistic aspects of cholesterol absorption were probed using compounds that block cholesterol absorption in hamsters. Sterol glycoside cholesterol absorption inhibitors, exemplified by L-166,143, (3 beta, 5 alpha,25R)-3-(4", 6"-bis2-fluoro-phenylcarbamoyl-B-D-cellobiosyl)oxy-spirostan -11-on e, potently blocked absorption of radioactive cholesterol, and the potencies of several analogs correlated with their ability to lower plasma cholesterol. Each molecule of L-166,143 blocked the uptake of 500 molecules of cholesterol, rendering it unlikely that the inhibitor interacts directly with the cholesterol or bile acid. Radiolabeled L-166,143 bound to the mucosa and binding was blocked by active, but not inactive, cholesterol absorption inhibitors. Subtle changes in the structure of sterol glycosides yielded large changes in their ability to block both cholesterol absorption and binding of radiolabeled L-166,143. Large species-to-species variation in potency was also observed. These lines of evidence support the interpretation that dietary cholesterol is absorbed via a specific transporter found in the intestinal mucosa. |
| Intestinal absorption of cholesterol, transport in the haemolymph, and incorporation into the fat body and Malpighian tubules of the larval dragonfly Aeshna cyanea Komnick, H. and U. Giesa (1994), Comp Biochem Physiol Comp Physiol 107(3): 553-7. Abstract: Doses of 1.5 mumol cholesteryl oleate ingested by Aeshna cyanea larvae were partially hydrolysed in the intestinal lumen and the liberated oleic acid absorbed, while free cholesterol and unhydrolysed cholesteryl oleate were eliminated in the faeces. Ingestion of 4-14Ccholesterol dissolved in olive oil revealed that the larvae also absorbed free cholesterol, the minor part of which (up to 12%) was esterified in the midgut epithelium. Absorption and esterification were markedly enhanced when the same dose of labelled cholesterol was administered in 20% aqueous bovine serum albumin. Radioactivity was rather slowly released into the haemolymph where it was nearly exclusively associated with free cholesterol apart from traces of labelled cholesteryl ester which maximally amounted to 2.9% after 15 days. In the fat body labelled cholesteryl ester maximally amounted to 65% after 15 days, while in the triacylglycerol-storing Malpighian tubules it remained below 1% at all time periods investigated. |
| Intestinal absorption of triglyceride and cholesterol. Dietary and pharmacological inhibition to reduce cardiovascular risk Ros, E. (2000), Atherosclerosis 151(2): 357-79. Abstract: Triglycerides and cholesterol are important biological lipids, and their excessive intake in the diet is relevant to the development of two prevalent cardiovascular risk factors, obesity and hypercholesterolemia. Because most lipids are essentially water-insoluble molecules, their transport within and absorption from the aqueous medium of intestinal contents is rather complex. This takes place in a series of orderly and interrelated steps, including emulsification, hydrolysis by specific esterases, micellar transport, mucosal absorption, re-synthesis of parent molecules in enterocytes, and assembly with apolipoproteins and other molecules to form chylomicrons, the secretory product of intestinal cells. Many of these processes, however, are not well characterized at the molecular level. While in health the intestinal absorption of triglycerides is very efficient, the same does not apply to cholesterol absorption. Besides being generally inefficient, cholesterol absorption is highly variable, with a between-subject variability that depends in part on genetic factors and an intra-individual variability, which may be modulated by physiological and dietary conditions. All of the sequential steps in intestinal lipid absorption can be interfered with by dietary components or drugs and thus are potential therapeutic targets for inducing a controlled malabsorption of triglyceride, useful in the treatment of obesity, or for rendering cholesterol absorption even more inefficient in an attempt to lower blood cholesterol levels. Nevertheless, intestinally derived cholesterol available to the liver exerts complex feedback regulation on whole-body cholesterol homeostasis that limits the efficacy of cholesterol absorption inhibitors to lower blood cholesterol. This review focuses first on present knowledge of the physiology of intestinal fat absorption, necessary to understand the ways to manipulate it in order to obtain the desired effects on dietary triglyceride and cholesterol disposition. The second part discusses old, present and future ways, both dietary and pharmacological. of interfering with cholesterol and triglyceride absorption to reduce blood cholesterol and energy acquisition, respectively. |
| Intestinal cholesterol absorption Dawson, P. A. and L. L. Rudel (1999), Curr Opin Lipidol 10(4): 315-20. Abstract: The strong association between intestinal cholesterol absorption and total plasma cholesterol level has renewed interest in the absorptive process and stimulated the generation of new animal models. Increasingly, new studies suggest that cholesterol absorption is genetically controlled and supports a protein-mediated mechanism for cholesterol uptake into the intestinal mucosal cell. Insights into potential mechanisms are predicted to lead to novel pharmacological approaches to inhibit cholesterol absorption. |
| Intestinal cholesterol absorption and NPC1-L1 Lambert, G., M. Chetiveaux, et al. (2004), Med Sci (Paris) 20(6-7): 636-8. |
| Intestinal cholesterol absorption: a pharmacological target for lowering of plasma cholesterol Catapano, A. L., L. Catapano, et al. (2004), Ital Heart J Suppl 5(10): 779-84. Abstract: A number of clinical studies clearly demonstrate the efficacy of hypocholesterolemic treatment in reducing incident cardiovascular events. The benefit appears to be proportional to the reduction of LDL cholesterol. Recent guidelines suggest an even more stringent target of 70 mg/dl for LDL cholesterol in high-risk subjects. Statins represent a very effective treatment of hypercholesterolemia, and the co-administration of drugs with complementary mechanisms of action, may represent an additional pharmacological tool in clinical practice to achieve the suggested targets for LDL lowering. In this short review we address the most recent discoveries in the physiological pathways of cholesterol absorption and identify the concept of dual inhibition as a therapeutic paradigm that may help in reaching the LDL cholesterol targets in clinical practice. |