| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol depletion reduces apical transport capacity in epithelial Madin-Darby canine kidney cells Prydz, K. and K. Simons (2001), Biochem J 357(Pt 1): 11-5. Abstract: Reduction of the cholesterol level in membranes of epithelial Madin-Darby canine kidney (MDCK) cells reverses the apical-to-basolateral transport ratio of the apical membrane marker protein influenza virus haemagglutinin and the secreted glycoprotein gp80. At the same time, basolateral transport of the vesicular stomatitis virus G protein is unaffected Keller and Simons (1998) J. Cell Biol. 140, 1357-1367. To investigate whether cholesterol depletion influences apical sorting mechanisms specifically, or apical transport capacity more generally, we studied the effect of cholesterol depletion on the secretion of three different classes of molecules from the apical and basolateral surfaces of MDCK cell layers: glycoprotein gp80, sulphated proteoglycans and proteins, and non-glycosylated rat growth hormone. In each case, cholesterol depletion reduced the fraction secreted to the apical medium and increased the fraction secreted basolaterally. The fact that this was observed for all sulphated proteins and proteoglycans and for the non-glycosylated rat growth hormone, which is randomly secreted in untreated cells, indicates that cholesterol depletion reduces the apical transport capacity, rather than interfering with specific recognition and sorting processes. |
| Cholesterol depletion results in site-specific increases in epidermal growth factor receptor phosphorylation due to membrane level effects. Studies with cholesterol enantiomers Westover, E. J., D. F. Covey, et al. (2003), J Biol Chem 278(51): 51125-33. Abstract: In A431 cells, depletion of cholesterol with methyl-beta-cyclodextrin induced an increase in both basal and epidermal growth factor (EGF)-stimulated EGF receptor phosphorylation. This increase in phosphorylation was site-specific, with significant increases occurring at Tyr845, Tyr992, and Tyr1173, but only minor changes at Tyr1045 and Tyr1068. The elevated level of receptor phosphorylation was associated with an increase in the intrinsic kinase activity of the EGF receptor kinase, possibly as a result of the cyclodextrin-induced enhancement of the phosphorylation of Tyr845, a site in the kinase activation loop known to be phosphorylated by pp60src. Cholesterol and its enantiomer (ent-cholesterol) were used to investigate the molecular basis for the modulation of EGF receptor function by cholesterol. Natural cholesterol (nat-cholesterol) was oxidized substantially more rapidly than ent-cholesterol by cholesterol oxidase, a protein that contains a specific binding site for the sterol. By contrast, the ability of nat- and ent-cholesterol to interact with sphingomyelins and phosphatidylcholine and to induce lipid condensation in a monolayer system was the same. These data suggest that, whereas cholesterol-protein interactions may be sensitive to the absolute configuration of the sterol, sterol-lipid interactions are not. nat- and ent-cholesterol were tested for their ability to physically reconstitute lipid rafts following depletion of cholesterol. nat- and ent-cholesterol reversed to the same extent the enhanced phosphorylation of the EGF receptor that occurred following removal of cholesterol. Furthermore, the enantiomers showed similar abilities to reconstitute lipid rafts in cyclodextrin-treated cells. These data suggest that cholesterol most likely affects EGF receptor function because of its physical effects on membrane properties, not through direct enantioselective interactions with the receptor. |
| Cholesterol depletion suppresses the translational diffusion of class II major histocompatibility complex proteins in the plasma membrane Vrljic, M., S. Y. Nishimura, et al. (2005), Biophys J 88(1): 334-47. Abstract: Glycosylphosphatidylinositol (GPI)-linked and native major histocompatibility complex class II I-E(k) were used as probes to determine the effect of varying cholesterol concentration on the mobility of proteins in the plasma membrane. These proteins were imaged in Chinese hamster ovary cells using single-molecule fluorescence microscopy. Observed diffusion coefficients of both native and GPI-linked I-E(k) proteins were found to depend on cholesterol concentration. As the cholesterol concentration decreases the diffusion coefficients decrease by up to a factor of 7 for native and 5 for GPI-linked I-E(k). At low cholesterol concentrations, after sphingomyelinase treatment, the diffusion coefficients are reduced by up to a factor of 60 for native and 190 for GPI-linked I-E(k). The effect is reversible on cholesterol reintroduction. Diffusion at all studied cholesterol concentrations, for both proteins, appears to be predominantly Brownian for time lags up to 2.5 s when imaged at 10 Hz. A decrease in diffusion coefficients is observed for other membrane proteins and lipid probes, DiIC12 and DiIC18. Fluorescence recovery after photobleaching measurements shows that the fraction of immobile lipid probe increases from 8 to approximately 40% after cholesterol extraction. These results are consistent with the previous work on cholesterol-phospholipid interactions. That is, cholesterol extraction destroys liquid cholesterol-phospholipid complexes, leaving solid-like high melting phospholipid domains that inhibit the lateral diffusion of membrane components. |
| Cholesterol depletion upregulates involucrin expression in epidermal keratinocytes through activation of p38 Jans, R., G. Atanasova, et al. (2004), J Invest Dermatol 123(3): 564-73. Abstract: Cholesterol has been recently suggested to regulate the early steps of keratinocyte differentiation through lipid rafts. In many cell types, depletion of cholesterol activates signaling proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), or extracellular signal-regulated kinase (ERK) known to affect cell differentiation. In this study, we explored the effects of cholesterol depletion on the phenotype of cultured keratinocytes, using a treatment with methyl-beta-cyclodextrin (MbetaCD) to extract cholesterol and a treatment with lovastatin to inhibit cholesterol neosynthesis. Analysis of the expression of differentiation marker genes in early differentiating confluent cultures reveals that cholesterol depletion induces downregulation of keratin 14 (K14) and keratin 10 (K10) and upregulation of involucrin. MbetaCD treatment induces phosphorylation of EGFR, HER2, and ERK, but not HER3. Inhibition of EGFR with PD153035 impairs the MbetaCD-induced phosphorylation of EGFR, HER2, and ERK, but does not impair the alteration of K14, K10, or involucrin gene expression, indicating that other signaling proteins regulate this phenomenon. p38 has been suggested to regulate the expression of involucrin during keratinocyte differentiation. We found that MbetaCD treatment induces a prolonged phosphorylation of p38 in general and p38alpha in particular. An inhibition of p38 with PD169316 impairs the upregulation of involucrin mRNAs by a treatment with MbetaCD, but not by a p38delta-activating TPA treatment, which might suggest that cholesterol depletion alters involucrin gene expression through activation of p38alpha/beta. |
| Cholesterol deposition in atherosclerotic lesions Kruth, H. S. (1997), Subcell Biochem 28: 319-62. |
| Cholesterol deposition in macrophages: foam cell formation mediated by cholesterol-enriched oxidized low density lipoprotein Greenspan, P., H. Yu, et al. (1997), J Lipid Res 38(1): 101-9. Abstract: Oxidized low density lipoprotein (LDL) is thought to mediate the transformation of macrophages to cholesterol-rich foam cells. Yet convincing evidence for this process is lacking in vitro. We suggest that oxidized LDL-mediated foam cell formation is not seen in vitro because the cholesteryl ester content of LDL particles (oxidized in the presence of transition metals) is dramatically reduced. Thus, if oxidized LDL could be cholesterol-enriched prior to its addition to macrophages, this lipoprotein would be made more capable of inducing the cellular deposition of cholesteryl esters. When we enriched cupric sulfate-oxidized LDL with cholesterol by incubation of this lipoprotein with unesterified cholesterol/phosphatidylcholine liposomes and added it to mouse peritoneal macrophage cultures, we found that: a) the enrichment of oxidized LDL with cholesterol did not alter the extent of oxidized LDL degradation; b) the cells accumulated massive amounts of cholesteryl ester (148 microg/mg cell protein) and unesterified cholesterol (260 microg/mg cell protein) after 24 h of incubation; and c) Sephacryl S-1000 chromatography of the cholesterol-enriched oxidized LDL verified the formation of large oxidized LDL-unesterified cholesterol/phosphatidylcholine complexes. These results demonstrate that oxidized LDL, when cholesterol-enriched, can mediate the formation of macrophage foam cells in culture |
| Cholesterol deprivation affects the fluorescence properties of a ceramide analog at the Golgi apparatus of living cells Martin, O. C., M. E. Comly, et al. (1993), Proc Natl Acad Sci U S A 90(7): 2661-5. Abstract: Previous studies have established that a fluorescent analog of ceramide, N-7-(4-nitrobenzo-2-oxa-1,3-diazole) -6-aminohexanoyl-D-erythro-sphingosine (C6-NBD-Cer), is a vital stain for the Golgi apparatus and a useful tool for studying the sorting and transport of sphingolipids along the secretory pathway in animal cells. Here, we examine the effects of various culture conditions on labeling of the Golgi apparatus of human skin fibroblasts by C6-NBD-Cer and demonstrate that cholesterol deprivation affects the fluorescence properties of the probe at this organelle. Labeling of the Golgi apparatus by C6-NBD-Cer was dramatically reduced in cells grown in medium containing lipoprotein-deficient serum compared to cells grown in medium containing normal serum. Quantitative fluorescence microscopy showed that this apparent reduction in labeling resulted from accelerated photo-bleaching of the fluorescent analog. C6-NBD-Cer labeling of the Golgi apparatus was restored in cholesterol-deprived cells by stimulating endogenous cholesterol biosynthesis with mevalonic acid or by adding exogenous nonlipoprotein cholesterol or low density lipoprotein to the culture medium. In addition, when cells grown in medium containing normal serum were perforated and treated with cholesterol oxidase, an apparent reduction in labeling resulted, further implicating an intracellular pool of cholesterol in the potentiation of C6-NBD-Cer fluorescence. These results demonstrate that cytological studies using C6-NBD-Cer are affected by cholesterol deprivation and suggest that this fluorescent lipid may be used to monitor cholesterol at the Golgi apparatus of living cells. |
| Cholesterol derivative of a new triantennary cluster galactoside directs low- and high-density lipoproteins to the parenchymal liver cell Biessen, E. A., H. Vietsch, et al. (1994), Biochem J 302 (Pt 1): 283-9. Abstract: We have developed a new triantennary galactoside, in which the terminal galactose moieties are connected to the branching point of the cluster galactoside via a 20 A (2 nm) spacer TG(20A). In vitro binding studies have demonstrated that introduction of a 20 A spacer resulted in avid and specific binding of the triantennary galactoside to the asialoglycoprotein receptor on the parenchymal liver cell. Derivatization of this galactoside with a cholesterol moiety afforded a compound TG(20A)C that lowered the serum cholesterol concentration when injected into rats. In the present study we have evaluated the direct effect of TG(20A)C on the in vivo fate of high-density lipoprotein (HDL) and low-density lipoprotein (LDL). A direct association of TG(20A)C with HDL and LDL was observed on mixing these components. Incorporation of TG(20A)C into 125I-HDL and 125I-LDL significantly accelerated the serum decay and concomitantly stimulated the hepatic uptake of these lipoproteins in rats. The liver uptake of TG(20A)C-loaded 125I-HDL or 125I-LDL could be inhibited by 81% and 82% respectively by preinjection of 150 mg of N-acetylgalactosamine, indicating that the enhanced liver uptake proceeded via galactose-specific receptors. More than 96% of the hepatic uptake of TG(20A)C-loaded 125I-HDL could be attributed to the parenchymal cell. Surprisingly, the parenchymal cell also accounted for 93% of the liver association of TG(20A)C-loaded 125I-LDL, suggesting that TG(20A)C stimulates the uptake and processing of both lipoproteins by the asialoglycoprotein receptor on the parenchymal liver cell. This contrasts with earlier data indicating that a triantennary cluster galactoside provided with a 4 A spacer between the terminal galactose moieties and the branching point of the dendrite stimulated hepatic uptake of LDL via the Kupffer cells. The parenchymal cell is the only liver cell type that is capable of irreversibly removing cholesterol from the body in the form of bile acids. The above results imply that administration of TG(20A)C not only facilitates the hepatic uptake of lipoprotein-derived cholesterol (esters) but also their elimination from the body. In addition, it might be possible to utilize TG(20A)C as a targeting device to selectively deliver large drug carriers and possibly genes to the parenchymal liver cell. |
| Cholesterol derivative of a new triantennary cluster galactoside lowers serum cholesterol levels and enhances secretion of bile acids in the rat Biessen, E. A., H. Vietsch, et al. (1995), Circulation 91(6): 1847-54. Abstract: BACKGROUND: Previous studies have demonstrated that cholesterol-derivatized galactosides exert a hypocholesterolemic effect by inducing hepatic uptake of atherogenic lipoproteins by means of galactose-recognizing receptors in the liver. However, a prolonged infusion of high concentrations of these compounds was required for this effect, possibly because of low affinity for the galactose-recognizing asialoglycoprotein receptor on the parenchymal liver cell. METHODS AND RESULTS: We have designed a new series of triantennary galactosides to optimize the affinity and specificity for this receptor. The affinity of a triantennary galactoside for the asialoglycoprotein receptor appeared to be dramatically enhanced by proper spacing of the three terminal galactose groups. In rats, a single injection of N-tris-O-(3,6,9-trioxaundecanyl-beta-D-galacto- pyranosyl)methoxymethylmethyl-N alpha-1-(6-(5-cholesten-3 beta- yloxy)glycyl)adipylglycinamide TG(20A)C, the cholesterol derivative of the most selective galactoside, causes a dose-dependent decrease of < or = 45% in the serum cholesterol concentration (P <.001). This decrease is mainly attributed to a decrease in the level of serum HDL (P =.0066) and, to a lesser extent, serum LDL (P =.036). In addition, TG(20A)C strongly enhances the bile-acid secretion in rats during the first 2 hours after administration, which indicates that TG(20A)C-induced clearance of cholesterol from the bloodstream is efficiently coupled to hepatic bile-acid secretion. CONCLUSIONS: We conclude that TG(20A)C efficiently directs lipoproteins that contain cholesterol to the liver at a 30-fold-lower concentration than previously developed cholesterol-derived cluster galactosides. This newly developed approach to lower cholesterol levels may prove valuable for familial hypercholesterolemic patients or those with familial defective apolipoprotein B-100 who do not respond or who respond insufficiently, respectively, to conventional therapies. |
| Cholesterol derivative of poly(ethylene glycol) inhibits clathrin-independent, but not clathrin-dependent endocytosis Ishiwata, H., S. B. Sato, et al. (1997), Biochim Biophys Acta 1359(2): 123-35. Abstract: The effect of poly(ethylene glycol) cholesteryl ethers (PEG(n)-Chols) with two different numbers of units (n = 50 and 200) in the hydrophilic PEG moiety on cellular endocytic activity was studied on HT-1080 cells. The amphipathic molecules were soluble in aqueous solution. When fluorescein derivatives of PEG-Chols (one fluorescein at the distal end of PEG) were incubated with the cells in culture, the cellular fluorescence was localized at the plasma membrane level and in intracellular vesicles. Fluorescence quantification indicated that for the same external concentration, twice more FPEG(50)-Chol than FPEG(200)-Chol was associated with the cells under the same conditions. Regardless of the length of PEG moiety, PEG-Chols' interaction with cells reduced the endocytic internalization of a fluid phase marker, horseradish peroxidase (HRP) depending on the cell-associated amount. In contrast, internalization of 125I-labeled epidermal growth factor (EGF) through receptor-mediated endocytosis did not change upon incubation with PEG(50)-Chol. The effect of PEG(200)-Chol was also small, since EGF internalization showed a reduction of 10-20%, while at the same concentration as much as 80% of HRP uptake was inhibited. PEG(50)-Chol did not influence the internalization of a larger ligand, 125I-transferrin (Tfn). However, in the presence of PEG(200)-Chol, the uptake of 125I-Tfn decreased remarkably, and yet, PEG(200)-Chol has no influence on the binding and internalization of a monoclonal antibody directed toward the ectodomain of the Tfn-receptor. These results suggested that incorporation of PEG-Chols in the outer monolayer of the plasma membrane specifically inhibited clathrin-independent, but not clathrin-dependent endocytosis. |
| Cholesterol detection, diagnosis and evaluation Ranade, V. (1993), Int J Clin Pharmacol Ther Toxicol 31(7): 313-21. Abstract: Children with parents who have premature cardiovascular disease often have high serum cholesterol levels. In order to prevent the formation of atherosclerotic lesions in the coronary arteries, efforts are called for identifying, treating and monitoring individual children and adolescents who have high serum cholesterol levels. The screening of children should be performed in the context of their continuing health care and particularly, adolescents who smoke cigarettes, have high blood pressure, or consume excessive amounts of saturated fatty acids, total fat and cholesterol and who are overweight should be subjected to cholesterol testing. On the basis of the data presented in this article, it will be prudent to test high serum cholesterol in all young people whose parents have a total serum cholesterol exceeding 240 mg/dl. A total serum cholesterol level of equal to or greater than 200 mg/dl or an LDL cholesterol level of equal to or greater than 130 mg/dl when associated with family history or parental hypercholesterolemia warrants further evaluation. Children and adolescents with high LDL cholesterol levels that are equal to or greater than 130 mg/dl should be considered to be possible secondary causes of hypercholesterolemia and therefore continuous monitoring and clinical evaluation of this population may be necessary. Other factors such as familial hyperlipidemia, hypoalphalipoproteinemia, diabetes and high alcohol intake also need careful assessment. |
| Cholesterol determination and age Donkerlo, T. W. (1990), Ned Tijdschr Geneeskd 134(45): 2203-4. |
| Cholesterol determination at conscription. A method to identify persons with high risk of developing cardiovascular disease Nygard, O. K., G. von der Lippe, et al. (1995), Tidsskr Nor Laegeforen 115(26): 3249-53. Abstract: In the adult population, serum cholesterol level and risk of cardiovascular disease are related to some extent to habits and lifestyle established at an early age. We have estimated serum total cholesterol levels by means of a dry chemical method and have collected information on established cardiovascular risk factors among 1,203 young Norwegian men at conscription. 30 of the recruits with the highest serum cholesterol levels were later examined in the hospital's out-patient clinic. A total of 30.8% of the recruits were daily smokers. Mean serum total cholesterol was 4.05 mmol/l with a 97.5 percentile value of 6.31 mmol/l. The prevalence of coronary heart disease among parents was significantly higher among recruits from the upper cholesterol quintile (4.2%) compared with those in the lowest quintile (0.8%) (p = 0.02). These findings show that cholesterol screening at conscription is feasible and can be used to identify a group of men at high risk of subsequently developing cardiovascular disease. |
| Cholesterol determination in ambulatory general practice within the scope of the Brugg/AG quality circle Ledergerber, P. P. and J. Steurer (2000), Schweiz Rundsch Med Prax 89(36): 1413-21. Abstract: Findings of studies designated by the acronyms 45, WOSCOP, LIPID and CARE have provided data that led physicians to rethink their "cholesterol testing behavior." Twelve physicians participated in a study conducted in cooperation with the quality circle of the Brugg region in Aargau. Each doctor collected data from the files of 100 patients and filled in a questionnaire. Cardiovascular risk factors and arteriosclerotic secondary illnesses were compiled along with demographic data. Moreover, information was gathered on whether the patient's cholesterol levels had been checked within the last five years. In total, 1183 questionnaires were evaluated, comprising 691 women and 492 men with an average age of 48.6 years. Cholesterol levels had been determined within the last five years in 61.2%. The individual testing behavior of the physicians varied. One-third tested all three blood lipid values (total cholesterol, HDL and triglyzerides) with an equivalent frequency. By contrast, one-third primarily only determined total cholesterol. The last one-third mostly tested total cholesterol and triglyzeride levels. The frequency of serum lipid tests increased proportionally to the number of risk factors. Cholesterol levels were tested less frequently (approx. 55%) in smokers and patients who never practiced sports than in patients with other risk factors (approx. 85%). The testing rate increased proportionally to the increasing number of arteriosclerotic secondary illnesses, but did not reach the one-hundred percent mark until 3 secondary illnesses were involved. Dietary counseling was the primary therapeutic intervention; medication was prescribed with a much rarer frequency. Although 75% of the patients with arteriosclerotic secondary illnesses had measurably higher cholesterol levels (> 5.2 mm/l), approx. one-third of the patients with coronary heart disease received therapy with cholesterol-lowering drugs as compared to only 16% of the patients with peripheral occlusive arterial disease. The conclusions that we can draw from these results for clinical practice are: if cholesterol levels are to be determined in order to evaluate a patient's cardiovascular risk, HDL cholesterol levels should also be tested since the ratio of these two values is a good predictor. To date, triglyzeride levels have not been identified as relevant risk factors for vascular events. Physicians evaluated the other risk factors variably, in particular with regard to obesity. For clinical practice, the potential risk factor of lack of exercise should be defined more accurately. In patients with clinically manifest arteriosclerotic secondary illnesses, serum lipids should be tested routinely and appropriate therapy induced when required. |
| Cholesterol determination methods (a literature review) Koloskova, S. V., A. L. Lobachev, et al. (2004), Klin Lab Diagn(1): 3-9. |
| Cholesterol determinations from skin puncture and venous blood have similar imprecisions Dorner, K. and D. Dorn-Zachertz (1991), Eur J Clin Chem Clin Biochem 29(6): 411-3. Abstract: Comparison of cholesterol values from venous blood and skin puncture blood is difficult, because biological differences between both materials may be concealed or increased by the preanalytical imprecision of skin puncture. In 12 adults, we studied the variance of cholesterol and urea determination in 8 blood samples obtained by the puncture of 8 fingers and compared the results with the 8-fold determination of a venous sample drawn simultaneously. Our results show that the additional imprecision of skin puncture is low, and that the differences are not statistically significant. The mean values for cholesterol were 3.9% lower in skin puncture plasma than in venous plasma, whereas the mean values for urea were very similar. |
| Cholesterol detoxification by the nuclear pregnane X receptor Kliewer, S. A. (2005), Proc Natl Acad Sci U S A 102(8): 2675-6. |
| Cholesterol dictates the freedom of EGF receptors and HER2 in the plane of the membrane Orr, G., D. Hu, et al. (2005), Biophys J 89(2): 1362-73. Abstract: The flow of information through the epidermal growth factor receptor (EGFR) is shaped by molecular interactions in the plasma membrane. The EGFR is associated with lipid rafts, but their role in modulating receptor mobility and subsequent interactions is unclear. To investigate the role of nanoscale rafts in EGFR dynamics, we used single-molecule fluorescence imaging to track individual receptors and their dimerization partner, human epidermal growth factor receptor 2 (HER2), in the membrane of human mammary epithelial cells. We found that the motion of both receptors was interrupted by dwellings within nanodomains. EGFR was significantly less mobile than HER2. This difference was likely due to F-actin because its depolymerization led to similar diffusion patterns between the EGFR and HER2. Manipulations of membrane cholesterol content dramatically altered the diffusion pattern of both receptors. Cholesterol depletion led to almost complete confinement of the receptors, whereas cholesterol enrichment extended the boundaries of the restricted areas. Interestingly, F-actin depolymerization partially restored receptor mobility in cholesterol-depleted membranes. Our observations suggest that membrane cholesterol provides a dynamic environment that facilitates the free motion of EGFR and HER2, possibly by modulating the dynamic state of F-actin. The association of the receptors with lipid rafts could therefore promote their rapid interactions only upon ligand stimulation. |
| Cholesterol diet enhances daily rhythm of Pai-1 mRNA in the mouse liver Kudo, T., E. Nakayama, et al. (2004), Am J Physiol Endocrinol Metab 287(4): E644-51. Abstract: Myocardial infarction frequently occurs in the morning, a phenomenon in part resulting from the downregulation of fibrinolytic activity. Plasminogen activator inhibitor-1 (PAI-1) is a key factor behind fibrinolytic activity, and its gene expression is controlled under the circadian clock gene in the mouse heart and liver. Hypercholesterolemia has been associated with impaired fibrinolysis due to enhanced PAI-1 activity, which has also been implicated in atherosclerosis. The aim of this study was to decipher whether the Pai-1 gene is still expressed daily with hypercholesterolemia. Hypercholesterolemia (1% cholesterol diet) did not significantly affect the daily expression of clock genes (Per2 and Bmal1) and clock-controlled genes (Dbp and E4bp4) in the liver (P > 0.05); however, daily expression of the Pai-1 gene and Pai-1 promoter regulating factor genes such as Nr4a1 was significantly upregulated (P < 0.01). Daily restricted feeding for 4 h during the day reset the gene expression of Per2, Pai-1, Nr4a1, and Tnf-alpha. Lesion of the suprachiasmatic nucleus, the location of the main clock system, led to loss of Per2 and Pai-1 daily expression profiles. In the present experiments, we demonstrated that hypercholesterolemia enhanced daily expression of the Pai-1, Tnf-alpha, and Nr4a1 genes in the mouse liver without affecting clock and clock-controlled genes. Therefore, the risk or high frequency of acute atherothrombotic events in the morning still seems to be a factor that may be augmented under conditions of hypercholesterolemia. |
| Cholesterol diet followed by normal diet alters functional and metabolic responses in rabbit aorta Ragazzi, E., L. Pandolfo, et al. (1990), Artery 17(2): 71-83. Abstract: Male New Zealand rabbits were fed a high cholesterol (1%) diet for 8 weeks followed by a normal diet for 8 additional weeks. Rabbits on normal diet were used as controls. Serum cholesterol, elevated at the end of the cholesterol feeding period, returned to normal at the time of observation. Aortic wall lesions were severe and vessel wall cholesterol in the thoracic aorta was approximately 10 times the level in control animals. In vitro, thoracic aortic rings were used to measure contractile response to noradrenaline (NOR); no difference in response was found between normal and treated rabbits. Rings pre-contracted with NOR, were exposed to acetylcholine (Ach), ATP and NaNO2. Proximal and distal rings from normal animals showed a dose-dependent relaxation response to all agents, though maximal dilation occurred at an intermediate concentration of Ach. The rings from treated rabbits relaxed normally in response to NaNO2, but ATP relaxation was reduced in proximal and distal rings and Ach induced a contractile response. HPLC analysis of tissue extracts from aortic arch and distal thoracic aorta showed reduced ATP, ADP, GTP and GDP, and increased AMP. These changes resulted in a reduced energy charge and a reduction in total adenine nucleotides. The data indicate that cholesterol feeding, followed by normal diet, causes severe alterations of aortic vessel wall and that at an advanced stage of the diet-induced experimental disease energy metabolism and endothelium dependent vasodilation remain impaired even in the presence of normal serum lipids. |