Cholesterol Journal Articles

Record 11161 to 11180

Role of the intestinal acyl-CoA:cholesterol acyltransferase activity in the hyperresponse of diabetic rats to dietary cholesterol
Maechler, P., C. B. Wollheim, et al. (1992), J Lipid Res 33(10): 1475-84.
Abstract: Contrary to normal rats, diabetic rats are known to develop marked hypercholesterolemia when fed a cholesterol-enriched diet. The triggering factor involved in this hyperresponse has not been identified. With the aim of clarifying the role of the intestinal acyl-CoA:cholesterol acyltransferase (ACAT), we studied the effects of a high fat diet and the changes of intestinal ACAT activity during the early development of streptozotocin-diabetes in rats. Feeding diabetic rats with a diet enriched in cholesterol and saturated fat produced an increase in plasma and in tissue cholesterol as early as 3 days after streptozotocin injection in the absence of hyperphagia. Under these experimental conditions, treatment with insulin or with the ACAT inhibitor CL-277082 significantly reduced the plasma cholesterol to levels measured in nondiabetic rats fed the same high fat diet. An increase in 14Ccholesterol in plasma very low density lipoprotein was observed after oral administration of labeled cholesterol to 3-day diabetic rats. In parallel experiments, the direct measurement of small intestine microsomal ACAT activity revealed an increase, averaging 288% in diabetic rats 3 days after diabetes induction. This change in ACAT activity occurred simultaneously with an increase in plasma glucagon and was normalized by insulin treatment. The induction of intestinal ACAT activity in diabetic rats, its modulation by insulin, and the hypocholesterolemic effects of insulin or CL-277082 treatment clearly indicate that ACAT activity plays a major role in the initiation of diabetes-associated hypercholesterolemia.

Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse
Osono, Y., L. A. Woollett, et al. (1995), J Clin Invest 95(3): 1124-32.
Abstract: These studies were undertaken to quantify cholesterol balance across the plasma space and the individual organs of the mouse, and to determine the role of the low density lipoprotein receptor (LDLR) in these two processes. In the normal mouse (129 Sv), sterol was synthesized at the rate of 153 mg/d per kg body weight of which 78% occurred in the extrahepatic tissues while only 22% took place in the liver. These animals metabolized 7.1 pools of LDL-cholesterol (LDL-C) per day, and 79% of this degradation took place in the liver. Of this total turnover, the LDLR accounted for 88% while the remaining 12% was receptor independent. 91% of the receptor-dependent transport identified in these animals was located in the liver while only 38% of the receptor-independent uptake wsa found in this organ. When the LDLR was deleted, the LDL-C production rate increased 1.7-fold, LDL-C turnover decreased from 7.1 to 0.88 pools/d, and the plasma LDL-C level increased 14-fold, from 7 to 101 mg/dl. Despite these major changes in the circulating levels of LDL-C, however, there was no change in the rate of cholesterol synthesis in any extrahepatic organ or in the whole animal, and, further, there was no change in the steady-state cholesterol concentration in any organ. Thus, most extrahepatic tissues synthesize their daily sterol requirements while most LDL-C is returned directly to the liver. Changes in LDLR activity, therefore, profoundly alter the plasma LDL-C concentration but have virtually no affect on cholesterol balance across any extrahepatic organ, including the brain.

Role of the National Cholesterol Education Program Adult treatment panel III guidelines in managing dyslipidemia
Talbert, R. L. (2003), Am J Health Syst Pharm 60(13 Suppl 2): S3-8; quiz S25.
Abstract: Using recently updated guidelines to evaluate and manage lipid disorders is discussed. Coronary heart disease (CHD) is a costly chronic condition associated with significant morbidity and mortality. Epidemiologic data further indicate that dyslipidemia and associated conditions, which may lead to CHD, are grossly undertreated. In 2001, the third National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) released updated guidelines for the evaluation and treatment of lipid disorders. Significant changes to the updated guidelines include designation of a CHD risk equivalent category identifying patients who require aggressive management, recommendation of Framingham-based CHD risk assessment in patients with multiple risk factors, revised target levels for several of the lipids and lipoproteins, and criteria for the identification of patients with the metabolic syndrome. Low-density lipoprotein cholesterol (LDL-C) continues to be the primary target of therapy. In addition, non-high-density lipoprotein cholesterol (HDL-C) is now defined as a secondary treatment target in patients with hypertriglyceridemia. Increased emphasis is placed on the metabolic syndrome, low HDL-C levels, and the presence of multiple and emerging risk factors in guiding the intensity of therapy. The NCEP ATP III guidelines acknowledge challenges in implementing and maintaining patient adherence to both lifestyle changes and pharmacotherapy regimens and provide strategies for increasing treatment success. Implementation of these new guidelines will likely enhance identification, management, and treatment success rates among patients at risk for CHD in the United States.

Role of the plasma membrane in cholesterol esterification in rat hepatoma cells
Lange, Y., F. Strebel, et al. (1993), J Biol Chem 268(19): 13838-43.
Abstract: The source of the cholesterol used for ester synthesis by cultured rat hepatoma cells was examined. The activities synthesizing and esterifying cholesterol co-distributed with RNA at a high buoyant density, presumably in the rough endoplasmic reticulum (RER). Cholesterol mass was undetectable in the RER, and the transfer of cholesterol synthesized in the RER to the cell surface was more than 100 times greater than was its esterification. Similarly, essentially all of the cholesterol liberated from ingested intracellular lipoproteins was recovered at the cell surface. The plasma membranes, which contained approximately 87% of cell cholesterol, provided > 100 times more cholesterol for esterification in the RER than did nascent cholesterol. The supply of cholesterol was rate-limiting for esterification in cell homogenates. Prior oxidation of plasma membrane cholesterol in intact cells reduced the acyl-CoA:cholesterol acyltransferase activity in isolates proportionately. Finally, cholesterol in hepatoma plasma membranes was a far better substrate for in vitro esterification than was that in fibroblast plasma membranes, red blood cell ghosts, or liposomes. We conclude that the level of saturation of acyl-CoA:cholesterol acyltransferase, controlled principally through the bidirectional movement of the substrate between plasma membranes and RER, plays a major role in the regulation of cholesterol esterification.

Role of the protein kinase C signaling pathway in high-density lipoprotein receptor-mediated efflux of intracellular cholesterol
Mendez, A. J., J. F. Oram, et al. (1991), Trans Assoc Am Physicians 104: 48-53.
Abstract: These studies provide evidence that binding of HDL3 to the HDL receptor stimulates translocation and efflux of intracellular cholesterol through mechanisms involving the activation of protein kinase C. This conclusion is supported by data demonstrating that HDL is able to increase cell diacylglycerol levels and activate protein kinase C. Sphingosine, a protein kinase C inhibitor, was able to inhibit HDL3-mediated cholesterol translocation and efflux, further suggesting a role for protein kinase C in HDL receptor-dependent cholesterol efflux. Inhibition of HDL-mediated diacylglycerol formation by pertussis toxin suggests the possible involvement of a G protein-activated phospholipase. Further studies are needed to understand how activation of protein kinase C promotes cholesterol translocation and to identify the target proteins for protein kinase C phosphorylation.

Role of the steroidogenic acute regulatory (StAR) protein in the delivery of cholesterol to the inner mitochondrial membrane
Sugawara, T. (1997), Tanpakushitsu Kakusan Koso 42(13): 2081-8.

Role of volatile oil pretreatment and skin cholesterol on permeation of ion-paired diclofenac sodium
Sapra, B., S. Gupta, et al. (2000), Indian J Exp Biol 38(9): 895-900.
Abstract: This study was designed to investigate the influence of volatile oil pretreated skin on in vitro permeation from films containing ionized and dodecylamine ion-paired diclofenac sodium (DS). The involvement of skin cholesterol was investigated to determine its possible role in enhancing the permeation of ion-paired DS. Cardamom oil produced the maximum (10 x) in vitro permeation enhancement for ion-paired DS. The carrageenan induced rat paw oedema reduction (up to 12 hr) by cardamom oil was comparable to that of diclofenac injection (s c). Leaching of cholesterol from excised skin in addition to increased partition coefficient following volatile oil skin pretreatment appears to be responsible for in vitro permeation enhancement of DS. Whereas, a mild barrier perturbation effect due to altered cholesterol levels following pretreatment with volatile oils appears to increase the permeation of ion-paired DS across viable skin, thereby producing significant reduction of carrageenan induced paw oedema.

Roles of acyl-coenzyme A: cholesterol acyltransferase (ACAT) isozymes
Miyazaki, A. and S. Horiuchi (1999), Tanpakushitsu Kakusan Koso 44(8 Suppl): 1312-8.

Roles of acyl-coenzyme A:cholesterol acyltransferase-1 and -2
Chang, T. Y., C. C. Chang, et al. (2001), Curr Opin Lipidol 12(3): 289-96.
Abstract: Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an intracellular enzyme that produces cholesteryl esters in various tissues. In mammals, two ACAT genes (ACAT1 and ACAT2) have been identified. Together, these two enzymes are involved in storing cholesteryl esters as lipid droplets, in macrophage foam-cell formation, in absorbing dietary cholesterol, and in supplying cholesteryl esters as part of the core lipid for lipoprotein synthesis and assembly. The key difference in tissue distribution of ACAT1 and ACAT2 between humans, mice and monkeys is that, in adult human liver (including hepatocytes and bile duct cells), the major enzyme is ACAT1, rather than ACAT2. There is compelling evidence implicating a role for ACAT1 in macrophage foam-cell formation, and for ACAT2 in intestinal cholesterol absorption. However, further studies at the biochemical and cell biological levels are needed in order to clarify the functional roles of ACAT1 and ACAT2 in the VLDL or chylomicron synthesis/assembly process.

Roles of deoxycholate and arachidonate in pathogenesis of cholesterol gallstones in obese patients during rapid loss of weight
Marks, J. W., G. G. Bonorris, et al. (1991), Dig Dis Sci 36(7): 957-60.
Abstract: Our aim was to examine the relationship between biliary deoxycholate and arachidonate in obese patients and the relationship of deoxycholate and arachidonate to the stimulation of biliary mucous glycoprotein among obese patients predisposed to cholesterol gallstones. Thirty-four obese patients predisposed to cholesterol gallstones by a weight-reducing diet (520 kcal/day) received placebo, ursodiol (1200 mg/day), or aspirin (1300 mg/day). Duodenal bile was collected prior to beginning the diet and at four weeks. There was no correlation between deoxycholate and arachidonate among the 34 patients before beginning the diet. With placebo, deoxycholate decreased while arachidonate and glycoprotein increased. With ursodiol, deoxycholate decreased while arachidonate decreased and glycoprotein did not change. With aspirin, there was no change in deoxycholate but a decrease in arachidonate and no change in glycoprotein. Our data do not support a role for biliary deoxycholate in the regulation of biliary arachidonate. Our data do support a role for arachidonate, but not deoxycholate, in the regulation of biliary glycoprotein during the formation of cholesterol gallstones.

Roles of plasma lipid transfer proteins in reverse cholesterol transport
Yamashita, S., N. Sakai, et al. (2001), Front Biosci 6: D366-87.
Abstract: Plasma lipid transfer proteins include plasma cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP). Plasma CETP facilitates the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to apolipoprotein (apo) B-containing lipoproteins, and is a key protein in reverse cholesterol transport which protects vessel walls from atherosclerosis. The importance of plasma CETP in lipoprotein metabolism was highlighted by the discovery of CETP-deficient subjects with a marked hyperalphalipoproteinemia (HALP). The deficiency of CETP causes various abnormalities in the concentration, composition, and functions of both HDL and low-density lipoprotein (LDL). Although the significance of CETP in terms of atherosclerosis has been controversial, the in vitro evidence showed that large CE-rich HDL particles in CETP deficiency are defective in cholesterol efflux. Recent epidemiological studies in Japanese-Americans and in Omagari area where HALP subjects with the intron 14 splicing defect of CETP gene are markedly frequent, have demonstrated an increased incidence of coronary atherosclerosis in CETP-deficient patients. Similarly, scavenger receptor BI (SR-BI) knockout mice show a marked increase in HDL-cholesterol but accelerated atherosclerosis in atherosclerosis-susceptible mice. Thus, CETP deficiency is a state of impaired reverse cholesterol transport which may possibly lead to the development of atherosclerosis. PLTP transfers phospholipids from triglyceride (TG)-rich lipoproteins to HDL during lipolysis. Human plasma PLTP has a 20% sequence homology to human CETP and human PLTP gene has a marked similarity in the exon-intron organization. Both CETP and PLTP belong to the lipid transfer/lipopolysaccharide binding protein (LBP) gene family, which also includes LBP and bactericidal/permeability-increasing protein (BPI). Although these 4 proteins possess different physiological functions, they share marked biochemical similarities. The current review will also focus on the molecular genetics and function of plasma lipid transfer proteins, including CETP and PLTP.

Roles of scavenger receptor BI and APO A-I in selective uptake of HDL cholesterol by adrenal cells
Williams, D. L., R. E. Temel, et al. (2000), Endocr Res 26(4): 639-51.
Abstract: Adrenal cells obtain cholesterol for steroid production via the selective uptake of cholesteryl ester (CE) from HDL particles, a process in which CE is transferred to the plasma membrane without degradation of the HDL particle. Although this process has been studied for two decades, only recently have the receptor and the HDL ligand been identified. Scavenger class B, type I, (SR-BI) is regulated by ACTH in adrenocortical cells in parallel with steroid production. Antibody to SR-BI blocks the uptake and utilization of HDL CE for steroid production in Y1-BS1 adrenal cells. The adrenal glands of SR-BI knockout mice are depleted in cholesterol providing complementary evidence that SR-BI is responsible for HDL CE accumulation in adrenal cells. SR-BI-mediated HDL CE selective uptake is a two-step process in which SR-BI first interacts with multiple sites in apoA-I with the amphipathic inverted alpha-helical repeat units of apoA-I serving as recognition motifs. This is followed by efficient CE transfer down its concentration gradient to the plasma membrane, a process requiring the extracellular domain of SR-BI. Other scavenger receptors bind HDL but do not afford the CE transfer step. Adrenal glands from apoA-I knockout mice lack CE stores, indicating that apoAI is essential for HDL selective uptake in vivo. ApoA-I knockout HDL particles bind normally to SR-BI but do not permit efficient CE transfer to the cell. These findings suggest that apoA-I has an important role in the transfer of HDL CE that goes beyond its function as a ligand for interaction with SR-BI.

RORalpha: an orphan nuclear receptor on a high-cholesterol diet
Willson, T. M. (2002), Structure (Camb) 10(12): 1605-6.
Abstract: A high-resolution X-ray crystal structure of the retinoic acid receptor-related orphan receptor (RORalpha; NR1F1), which reveals a molecule of cholesterol within the ligand binding pocket, is a breakthrough in functional analysis of this orphan nuclear receptor.

Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study
Paoletti, R., M. Fahmy, et al. (2001), J Cardiovasc Risk 8(6): 383-90.
Abstract: BACKGROUND: Rosuvastatin (Crestor), a new, highly efficacious statin, has demonstrated dose-dependent low-density lipoprotein cholesterol (LDL-C) reductions of up to 65% in a dose-ranging programme with doses of 1 to 80 mg. DESIGN: A randomized, double-blind multicentre trial compared rosuvastatin with commonly used starting doses of pravastatin and simvastatin to determine relative efficacy in LDL-C reduction and impact on other lipid parameters in primary hypercholesterolaemia. METHODS AND RESULTS: A total of 502 patients (greater-than-or-equal 18 years; LDL-C greater-than-or-equal 4.14 mmol/l 160 mg/dl and < 6.50 mmol/l 250 mg/dl and triglycerides less-than-or-equal 4.52 mmol/l 400 mg/dl) were randomized to 12 weeks of rosuvastatin 5 mg (n = 120) or 10 mg (n = 115), pravastatin 20 mg (n=137) or simvastatin 20 mg (n = 130). Rosuvastatin 5 and 10 mg reduced LDL-C by 42 and 49%, respectively, compared with 28% for pravastatin (P < 0.001 versus both rosuvastatin doses) and 37% for simvastatin (P < 0.01 versus rosuvastatin 5 mg; P < 0.001 versus 10mg). National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) goals were achieved by 87% of rosuvastatin 10mg patients, 71% of rosuvastatin 5mg patients, 53% of pravastatin patients, and 64% of simvastatin patients; similar proportions of patients achieved NCEP ATP III goals. European Atherosclerosis Society (EAS) goals were achieved by 83, 63, 20 and 50% of patients, respectively. All study treatments were well tolerated. CONCLUSIONS: Both doses of rosuvastatin were more effective than pravastatin and simvastatin in meeting NCEP ATP II and EAS LDL-C targets. Rosuvastatin 10 mg was more effective than pravastatin and simvastatin in meeting NCEP ATP III targets.

Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial
Ridker, P. M. (2003), Circulation 108(19): 2292-7.

Rosuvastatin is cost-effective in treating patients to low-density lipoprotein-cholesterol goals compared with atorvastatin, pravastatin and simvastatin: analysis of the STELLAR trial
Hirsch, M., J. C. O'Donnell, et al. (2005), Eur J Cardiovasc Prev Rehabil 12(1): 18-28.
Abstract: BACKGROUND: Rosuvastatin calcium (CRESTOR) has demonstrated superior efficacy in reducing low-density lipoprotein cholesterol (LDL-C). However, healthcare providers and authorities require information on its cost-effectiveness in the treatment of dyslipidaemia. DESIGN: A retrospective pharmacoeconomic analysis was performed using data from the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. The cost-effectiveness of rosuvastatin 10-40 mg was compared with atorvastatin 10-80 mg, pravastatin 10-40 mg and both branded and generic simvastatin 10-80 mg in achieving Third Joint European Task Force LDL-C goals in patients with hypercholesterolaemia. METHODS: The analysis was conducted from the perspective of the UK National Health Service, using clinical data from the STELLAR trial and drug acquisition costs. Cost-effectiveness was compared using incremental cost-effectiveness ratios (ICERs), with sensitivity analyses applied to both efficacy and cost parameters. RESULTS: In terms of patients achieving goal, rosuvastatin 10 mg dominated (was more effective at equal or lower cost) atorvastatin 10 and 20 mg, pravastatin 20 and 40 mg, branded simvastatin 10-80 mg and generic simvastatin 40 and 80 mg. Where rosuvastatin 10 mg did not dominate, ICERs ranged from 36 pounds sterling to 162 pounds sterling per extra patient to goal. Rosuvastatin 20 and 40 mg were cost-effective compared with milligram-equivalent and higher doses of other branded statins. Sensitivity analyses showed that the results were robust to variations in both statin efficacy and price. CONCLUSION: In patients with hypercholesterolaemia, rosuvastatin is a cost-effective statin option in treating to LDL-C goals.

Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin
Kleemann, R., H. M. Princen, et al. (2003), Circulation 108(11): 1368-74.
Abstract: BACKGROUND: Statins can exert anti-inflammatory antiatherosclerotic effects through an anti-inflammatory action, independent of lowering cholesterol. We addressed the question whether the anti-inflammatory activities of statins can reduce atherosclerosis beyond the reduction achieved by cholesterol lowering per se. METHODS AND RESULTS: Two groups of 20 female APOE*3-Leiden mice received either a high-cholesterol diet (HC) or a high-cholesterol diet supplemented with 0.005% (wt/wt) rosuvastatin (HC+R). The HC diet alone resulted in a plasma cholesterol concentration of 18.9+/-1.4 mmol/L, and administration of rosuvastatin lowered plasma cholesterol to 14.1+/-0.7 mmol/L. In a separate low-cholesterol (LC) control group, the dietary cholesterol intake was reduced, which resulted in plasma cholesterol levels that were comparable to the HC+R group (13.4+/-0.8 mmol/L). Atherosclerosis in the aortic root area was quantified after 24 weeks. As compared with the HC group, the LC group had a 62% (P<0.001) reduction in cross-sectional lesion area. When compared with the LC group, the HC+R group showed a further decrease in cross-sectional lesion area (80%, P<0.001), size of individual lesions (63%, P<0.05), lesion number (58%, P<0.001), monocyte adherence (24%, P<0.05), and macrophage-containing area (60%, P<0.001). Furthermore, rosuvastatin specifically suppressed the expression of the inflammation parameters MCP-1 and TNF-alpha in the vessel wall and lowered plasma concentrations of serum amyloid A and fibrinogen, independent of its cholesterol-lowering effect. CONCLUSIONS: Rosuvastatin reduces atherosclerosis beyond and independent of the reduction achieved by cholesterol lowering alone. This additional beneficial effect of rosuvastatin may be explained, at least partly, by its anti-inflammatory activity.

Rotational diffusion of a steroid molecule in phosphatidylcholine-cholesterol membranes: fluid-phase microimmiscibility in unsaturated phosphatidylcholine-cholesterol membranes
Pasenkiewicz-Gierula, M., W. K. Subczynski, et al. (1990), Biochemistry 29(17): 4059-69.
Abstract: Rotational diffusion of androstane spin-label (ASL), a sterol analogue, in various phosphatidylcholine (PC)-cholesterol membranes was systematically studied by computer simulation of steady-state ESR spectra as a function of the chain length and unsaturation of the alkyl chains, cholesterol mole fraction, and temperature for a better understanding of phospholipid-cholesterol and cholesterol-cholesterol interactions. Special attention was paid to the differences in the cholesterol effects on ASL motion between saturated and unsaturated PC membranes. ASL motion in the membrane was treated as Brownian rotational diffusion of a rigid rod within the confines of a cone imposed by the membrane environment. The wobbling rotational diffusion constant of the long axis, its activation energy, and the cone angle of the confines were obtained for various PC-cholesterol membranes in the liquid-crystalline phase. Cholesterol decreases both the cone angle and the wobbling rotational diffusion constant for ASL in all PC membranes studied in this work. The cholesterol effects are the largest in DMPC membranes. An increase of cholesterol mole fraction from 0 to 30% decreases the rotational diffusion constant by a factor of 9-15 (depending on temperature) and the cone angle by a factor of about 2. In dioleoyl-PC membranes, addition of 30 mol % cholesterol reduces both the rotational diffusion constant and the cone angle of ASL by factors of approximately 2.5 and approximately 1.3, respectively, while it was previously found to cause only modest effects on the motional freedom of phospholipid analogue spin probes Kusumi, A., Subczynski, W. K., Pasenkiewicz-Gierula, M., Hyde, J. S., & Merkle, H. (1986) Biochim. Biophys. Acta 854, 307-317. It is proposed that fluid-phase microimmiscibility takes place in dioleoyl-PC-cholesterol membranes at physiological temperatures, which induces cholesterol-rich domains in the membrane, partially due to the steric nonconformability between the rigid fused-ring structure of cholesterol and the 30 degrees bend at the C9-C10 cis double bond of the alkyl chains of dioleoyl-PC. The mechanism by which cholesterol influences the lipid dynamics in the membrane is different between saturated and unsaturated PC membranes.

Roundtable discussion. Achieving more aggressive low-density lipoprotein cholesterol lowering
Hunninghake, D. B., J. M. McKenney, et al. (2000), Am J Manag Care 6(19 Suppl): S1008-16.

Routine cholesterol screening in childhood
Robertson, L. D., Jr. (1990), Pediatrics 85(5): 894-5.

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Cholesterol Journal Articles