| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
| First Page | Previous Page | Next Page | Last Page |
| A new single-injury model of balloon angioplasty in cholesterol-fed rabbits: beneficial effect of hirudin and comparison with double-injury model Barry, W. L., P. J. Wiegman, et al. (1997), Lab Invest 77(1): 109-16. Abstract: Air desiccation endothelial injury followed by cholesterol feeding is known to induce focal femoral atherosclerosis in rabbits. We previously demonstrated the effectiveness of hirudin in limiting restenosis after balloon angioplasty (BA) in this double instrumentation injury (DI) model. In the present study, we sought to determine whether BA without prior air desiccation endothelial injury (single instrumentation injury (SI)) would lead to similar femoral lesions, and whether the response to this injury might also be limited by hirudin. Accordingly, 38 femoral arteries of cholesterol-fed rabbits underwent BA with (n = 18, DI group) or without (n = 20, SI group) prior air desiccation endothelial injury. Animals were killed 24 hours or 28 days after BA. Twenty-four hours after BA, the SI group (n = 10) had a significantly smaller percentage of cross-sectional area narrowing by plaque than the DI group (n = 8) (0% versus 42% +/- 9%, p = 0.008). However, 28 days after BA, the percentages of cross-sectional area narrowing by plaque in the SI (n = 10) and DI (n = 10) groups were similar (59% +/- 6% versus 68% +/- 1%, p = NS). The percentages of intima (16% +/- 3% versus 16% +/- 3%, p = NS) and media occupied by foam cells were also similar in the two groups. To test whether hirudin administration would limit arterial narrowing after injury in the SI model, we randomly assigned cholesterol-fed rabbits that had not undergone air desiccation injury to either bolus hirudin followed by repeat dosing 24 hours after BA or bolus heparin (150 U/kg) at the time of BA. The hirudin-treated group showed significantly less angiographic and histologic restenosis 28 days after BA, despite no difference in early (0 to 72 hours) cumulative cellular proliferation between the two groups. Thus, in the cholesterol-fed rabbit, plaque formation and foam cell accumulation are similar after BA of a non-air-desiccated (SI) or focally atherosclerotic (DI) artery. Thrombin inhibition with hirudin limits arterial narrowing after SI, further emphasizing the role of thrombin in neointimal growth after injury. |
| A new subgroup of lectin-bound biliary proteins binds to cholesterol crystals, modifies crystal morphology, and inhibits cholesterol crystallization Busch, N., F. Lammert, et al. (1995), J Clin Invest 96(6): 3009-15. Abstract: Biliary proteins inhibiting or promoting cholesterol crystallization are assumed to play a major role in cholesterol gallstone pathogenesis. We now report a new group of biliary proteins that bind to cholesterol crystals, modify crystal morphology, and inhibit cholesterol crystallization. Various glycoprotein mixtures were extracted from abnormal human gallbladder bile using lectin affinity chromatography on concanavalin A, lentil, and Helix pomatia columns and were added to supersaturated model bile. Independent of the protein mixtures added, from the cholesterol crystals harvested, the same four GPs were isolated having molecular masses of 16, 28, 63, and 74 kD, respectively. Each protein was purified using preparative SDS-PAGE, and influence on cholesterol crystallization in model bile was tested at 10 microg/ml. Crystal growth was reduced by 76% (GP63), 65% (GP16), 55% (GP74), and 40% (GP28), respectively. Thus, these glycoproteins are the most potent biliary inhibitors of cholesterol crystallization known so far. Evidence that the inhibiting effect on cholesterol crystallization is mediated via protein-crystal interaction was further provided from scanning electron microscopy studies. Crystals grown in presence of inhibiting proteins showed significantly more ordered structures. Incidence of triclinic crystals and regular aggregates was shifted from 30 to 70% compared with controls. These observations may have important implications for understanding the role of biliary proteins in cholesterol crystallization and gallstone pathogenesis. |
| A new theory to explain the genesis of petrous apex cholesterol granuloma Jackler, R. K. and M. Cho (2003), Otol Neurotol 24(1): 96-106; discussion 106. Abstract: OBJECTIVE: To propose a new hypothesis that attempts to explain the pathogenesis of petrous apex cholesterol granuloma (PA CG). CLASSIC OBSTRUCTION-VACUUM HYPOTHESIS: PA CGs form when mucosal swelling blocks the circuitous pneumatic pathways to the apical air cells. Trapped gas resorption results in a vacuum that triggers bleeding, and CG forms through anaerobic breakdown of blood products. PROBLEMS WITH THE CLASSIC (OBSTRUCTION-VACUUM) HYPOTHESIS: Impaired ventilation of mucosa-lined pneumatic tracts in the middle ear, mastoid, paranasal sinuses, and lung are very common, but CG is rare. The extraordinary levels of temporal bone pneumatization typically observed in PA CG cases is indicative of excellent ventilation and freedom from inflammatory mucosal disease. Were under pressure due to gas absorption alone sufficient to trigger hemorrhage, CG ought to be frequent in otitis media with effusion. PATIENTS: The opposite PA of 13 patients with PA CG compared with 31 highly pneumatic PAs in patients undergoing imagery for non-otologic reasons. MAIN OUTCOME MEASURE: The nature of the bony partition, as seen on computed tomography, between the PA air cell system and the adjacent marrow compartment. RESULTS: 4 of 13 PAs with CGs on the opposite side showed deficient septation between air cells and marrow, whereas this was not observed in any of the 31 extensively pneumatized normal ears. NEW HYPOTHESIS (EXPOSED MARROW): As cellular tracts penetrate the apex during young adulthood, budding mucosa invades and replaces hematopoietic marrow. The bony interface becomes deficient, with coaptation of richly vascular marrow and the mucosal air cell lining. Hemorrhage from the exposed marrow coagulates within the mucosal cells and occludes outflow pathways. Sustained hemorrhage from exposed marrow elements provides the engine responsible for the progressive cyst expansion. As the cyst expands, bone erosion increases the surface area of exposed marrow along the cyst wall. This exposed marrow theory explains the unique proclivity of the healthy and well-pneumatized PA to form a CG. |
| A nine-year chronic toxicity study of cadmium in monkeys. II. Effects of dietary cadmium on circulatory function, plasma cholesterol and triglyceride Akahori, F., T. Masaoka, et al. (1994), Vet Hum Toxicol 36(4): 290-4. Abstract: The effects of long-term (9 y) po administration of daily low doses of cadmium on blood pressure, heart rate, electrocardiogram and plasma cholesterol and triglyceride concentrations were examined in rhesus monkeys. Thirty-five male rhesus monkeys were divided into 5 groups and fed pelleted food containing cadmium chloride at dosages of 0, 3, 10, 30 or 100 micrograms cadmium/g food (= ppm). The 100 ppm group had increased blood pressure during the initial 1 1/2 y. Thereafter, the expected increase in blood pressure that occurred due to aging in the control and 3 ppm groups was not evident in the 100 ppm group. No changes attributable to cadmium were detected in pulse rates or in electrocardiograms. Plasma cholesterol in the 2 highest dosage groups and triglyceride in the 100 ppm group were slightly lower than in controls after 2 1/2 y. Long-term exposure to cadmium contributed to the development of elevated blood pressure during the first and second years and then inhibited the hypertension expected due to aging. |
| A noninstrumented quantitative test system and its application for determining cholesterol concentration in whole blood Allen, M. P., A. DeLizza, et al. (1990), Clin Chem 36(9): 1591-7. Abstract: A novel noninstrumented technology has been developed for quantifying analytes of clinical interest in biological fluids. Application of this technology is exemplified by the development of a quantitative cholesterol test with performance equivalent to state-of-the-art instrumented methods. The assay chemistry combines two separate processes located in different areas of a test strip: enzymatic action on serum cholesterol to produce hydrogen peroxide (5 x 10 mm enzyme reagent pad) and quantification of the hydrogen peroxide (5 x 70 mm measurement region). Color bands are formed in the measurement area through the use of a redox-coupled indicator system. The height of the color band on the strip is directly proportional to the sample cholesterol concentration. A one-step cassette contains all components necessary to run the test and includes blood filtration and automatic sample measurement, so that unmeasured finger-stick whole-blood specimens can be analyzed by the non-technically trained user. The test is complete in less than 15 min, is read visually like a thermometer, and gives results that are in excellent correlation with established instrumented methods. |
| A normal rate of cellular cholesterol removal can be mediated by plasma from a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency Berard, A. M., M. Clerc, et al. (2001), Clin Chim Acta 314(1-2): 131-9. Abstract: Lecithin-cholesterol acyltransferase (LCAT) is the major enzyme involved in the esterification of cholesterol in circulating plasma lipoproteins. In the present study, we describe the molecular defects in the LCAT gene and in lipoprotein metabolism of a 34-year-old patient presenting with features of classic familial LCAT deficiency. DNA sequencing revealed two separate point mutations in exon 3 of the patient's LCAT gene: a C to A substitution converting Tyr(83) to a Stop and a C to T transition converting an Arg(99) to a Cys. Digestion of patient PCR-amplified DNA with the restriction enzymes AccI and AciI established that the patient was a compound heterozygote for both mutations. In vitro expression of LCAT (Arg(99)-->Cys) in human embryonic kidney-293 cells demonstrated reduced expression, as well as reduced secretion and/or increased intracellular degradation of the mutant enzyme with significantly decreased alpha-LCAT specific activity, thus, establishing the functional significance of the LCAT (Arg(99)-->Cys) mutation. The plasma cholesterol esterification rate (CER, 2+/-0.3 nmol/ml/h), alpha-LCAT activity (2.9+/-0.1 nmol/ml/h) and LCAT concentration (0.3+/-0.1 microg/ml) were 2.9%, 2.3% and 6.1% that of normal subjects, respectively. Analysis of the patient's plasma lipid profile revealed reduced plasma concentrations of total cholesterol (111+/-0.5 mg/dl), HDL cholesterol (1.6+/-0.2 mg/dl), apolipoprotein (apo) A-I (52+/-4 mg/dl) and apo A-II (11+/-0.5 mg/dl). Nevertheless, for the first time, we demonstrate that the LCAT-deficient plasma is as efficient as control plasma in cholesterol efflux experiments performed with (3)H-cholesterol loaded fibroblasts. This result could explain the absence of premature atherosclerosis in this LCAT-deficient patient. |
| A novel cationic cholesterol derivative, its formulation into liposomes, and the efficient transfection of the transformed human cell lines HepG2 and HeLa Kisoon, N., M. Ariatti, et al. (2002), Drug Deliv 9(3): 161-7. Abstract: A novel cationic cholesterol derivative, 3betaN-(N',N',N'-trimethylaminopropane)-carbamoyl cholesterol iodide (Chol-Q), has been formulated with equimolar amounts of dioleoyl phosphatidylethanolamine (DOPE) into stable unilamellar liposomes up to 100 nm in size for DNA delivery into mammalian cells. When compared with similarly constituted liposomes containing the tertiary analogue 3betaN-(N',N'-dimethylaminopropane)-carbamoyl cholesterol (Chol-T) in a band shift assay, liposomes displayed similar DNA binding affinities and appeared to afford complete protection to plasmid DNA against serum nuclease catalysed degradation at liposome:DNA ratios (w/w) of 2.5:1, 5:1, and 10:1 in incubation mixtures containing 5% fetal bovine serum at 37 C for 90 min. Chol-Q liposomes were, however, markedly less toxic to cells in culture over a wide range of concentrations with cells numbering 76% of untreated controls at 37.5 microg/mL complete medium in the human hepatocellular carcinoma line HepG2 and 75% at 30 microg/mL in cervical carcinoma HeLa cells. At these levels of Chol-T liposomes, cell numbers were 37% and 15%, respectively. Gene transfer experiments with pSV2CAT and pRSVCAT plasmids in HepG2 cells showed maximum efficiency at a Chol-Q liposome:DNA ratio of 5:1 (w/w) and at a Chol-T liposome:DNA ratio of 10:1. In HeLa cells, both liposome preparations performed best at a ratio of 2.5:1. Differences in transfection efficiencies over the liposome range of 5-20 microg/ mL were rather less pronounced with Chol-Q lipoplexes suggesting a greater versatility of this system. |
| A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain Reid, P. C., N. Sakashita, et al. (2004), J Lipid Res 45(3): 582-91. Abstract: Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by progressive accumulation of cholesterol, gangliosides, and other lipids in the central nervous system and visceral organs. In the NPC1 mouse model, neurodegeneration and neuronal cell loss occur before postnatal day 21. Whether neuronal cholesterol accumulation occurs in vivo before the first signs of neuronal cell loss has not been demonstrated. In this report, we used the NPC1 mouse model and employed a novel cholesterol binding reagent, BC theta, that enabled us to visualize cellular cholesterol accumulation at a level previously unattainable. The results demonstrate the superiority of BC theta staining over conventional filipin staining in confocal microscopy and highlight several new findings. We show that at postnatal day 9, although only mild signs of neurodegeneration are detectable, significant neuronal cholesterol accumulation has already occurred throughout the NPC1 brain. In addition, although NPC1 Purkinje neurons exhibit a normal morphology at day 9, significant cholesterol accumulation within their extensive dendritic trees has occurred. We also show that in the thalamus and cortex of NPC1 mice, activated glial cells first appear at postnatal day 9 and heavily populate by day 22, suggesting that in NPC1 mice, neuronal cholesterol accumulation precedes neuronal injury and neuronal cell loss. |
| A novel cholesterol transfer protein in cardiac sarcolemma. Purification and initial characterization Santiago-Garcia, J. and J. Mas-Oliva (1991), Mol Cell Biochem 100(1): 51-9. Abstract: In contrast to several sterol carrier proteins isolated from soluble cytosolic fractions, a cholesterol transfer protein (CHTP) with an apparent molecular weight of 73,000 was isolated from a cardiac sarcolemmal fraction by detergent solubilization, column chromatography, and preparative electrophoresis using nondissociating polyacrylamide gels. This protein must be reconstituted into an artificial membrane in order to mediate cholesterol transfer activity. For the expression of its full activity, CHTP must also be present in the membrane in a multimeric form, since the monomer was shown not to be active. We believe this novel protein might represent an important molecule in the regulation of the homeostasis of cholesterol in cardiac sarcolemma. |
| A novel cholesteryl ester transfer protein promoter polymorphism (-971G/A) associated with plasma high-density lipoprotein cholesterol levels. Interaction with the TaqIB and -629C/A polymorphisms Le Goff, W., M. Guerin, et al. (2002), Atherosclerosis 161(2): 269-79. Abstract: The plasma cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport (RCT) by mediating the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to atherogenic ApoB-containing lipoproteins, including VLDL, IDL and LDL. We describe a new polymorphism located at position -971 in the human CETP gene promoter, which corresponds to a G/A substitution at a potential AvaI restriction site. The relationship between the -971G/A polymorphism, plasma lipid parameters and plasma CETP concentration was evaluated in the Etude Cas-Temoins de l'Infarctus du Myocarde (control-myocardial infarction cases) cohort, and revealed that the -971G/A polymorphism (A allele frequency: 0.491) was significantly associated with both plasma high-density lipoprotein cholesterol (HDL-C) levels and CETP concentration (P=0.006 and 0.009, respectively). Subjects with genotype -971GG displayed both low HDL-C levels and high plasma CETP concentration, while genotype -971AA subjects displayed the inverse relationship. Evaluation of potential interactions between the -971G/A and the -629C/A or TaqIB polymorphisms demonstrated that the -971G/A polymorphism interacts significantly with the functional -629C/A site and the TaqIB polymorphism with respect to plasma HDL-C levels (P=0.0014 and 0.012, respectively), but does not affect plasma CETP concentration. These results clearly suggest that the interaction between the 971G/A polymorphism and either the -629C/A or the TaqIB polymorphism on plasma CETP concentration is different than that implicated in HDL-C levels. Transient transfection of HepG2 cells revealed that the -971G/A polymorphism did not modulate transcriptional activity of the human CETP gene promoter. The -971G/A promoter polymorphism therefore constitutes a non-functional marker. Furthermore, the observed effects of the -971G/A polymorphism on both plasma CETP concentration and HDL-C levels are due to functional variants in linkage disequilibrium with it. Our findings strongly suggest the existence of as yet unidentified functional polymorphisms in the CETP gene promoter that could explain the association between specific polymorphisms of the CETP gene and both plasma HDL-C and CETP concentrations. |
| A novel device for measuring the effect of cholesterol on the release of oxygen from red blood cells into myocardial tissue O'Dea, T., H. Menchaca, et al. (2000), Biomed Instrum Technol 34(4): 283-92. Abstract: A novel method has been devised to measure the effect of cholesterol on the release of oxygen (O2) from the red blood cell (RBC) into a tailored environment, which can be made to mimic myocardial tissue. Cholesterol affects the cell membrane of the RBC and thus the release of O2 into tissue. While this is true of all tissue, the myocardium is especially sensitive because of its critical nature, its high O2 requirements, and the shortness of time that arterial blood spends in the muscle. Calculations are presented that show that the release time for O2 from RBCs is close to the residence time of the RBC in the coronary system. Sequential measurements of blood oxygen saturation (SO2) are made when oxygenated blood is subjected to conditions similar to those in the myocardium. The natural logarithm of the relative value of the SO2 at time t compared with the initial value of the SO2 can be fitted to a straight line whose slope is proportional to the parameters of the RBC membrane, the sample size, the hematocrit, and the diffusion parameters of the apparatus. This value is used to estimate the effects of cholesterol-lowering treatments on O2 release. This test will serve as a valuable adjunct to or replacement for stress tests in the evaluation of coronary artery disease, especially in patients whose physical conditions make standard stress testing painful or risky. |
| A novel high-amylose barley cultivar (Hordeum vulgare var. Himalaya 292) lowers plasma cholesterol and alters indices of large-bowel fermentation in pigs Bird, A. R., M. Jackson, et al. (2004), Br J Nutr 92(4): 607-15. Abstract: Hordeum vulgare var. Himalaya 292 is a new barley cultivar with altered starch synthesis and less total starch but more amylose, resistant starch (RS) and total and soluble NSP including beta-glucan. To determine its nutritional potential, young pigs were fed diets containing stabilised wholegrain flours from either Himalaya 292, Namoi (a commercial barley), wheat bran or oat bran at equivalent dietary NSP concentrations for 21 d. Serum total cholesterol was significantly lowered by the Himalaya 292 diet relative to wheat bran, indicating that Himalaya 292 retained its hypocholesterolaemic potential. In all groups SCFA concentrations were highest in the proximal colon and decreased towards the rectum. Digesta pH was lowest in the proximal colon and highest in the distal colon. Large-bowel and faecal pH were significantly lower in the pigs fed the barley and oat diets, indicating greater bacterial fermentation. Caecal and proximal colonic pH was lowest and SCFA pools highest in the pigs fed Himalaya 292. Total and individual SCFA were lowest in the mid- and distal colon of the pigs fed Himalaya 292 or oat bran. These data suggest the presence of more RS in Himalaya 292 and suggest that its fermentation was rapid relative to transit. Differences in faecal and large-bowel anaerobic, aerobic, coliform and lactic acid bacteria were relatively small, indicating a lack of a specific prebiotic action. These data support the potential of this novel barley cultivar to improve health through plasma cholesterol reduction and increased large-bowel SCFA production. |
| A novel lecithin-cholesterol acyltransferase antioxidant activity prevents the formation of oxidized lipids during lipoprotein oxidation Vohl, M. C., T. A. Neville, et al. (1999), Biochemistry 38(19): 5976-81. Abstract: Recent investigations suggest that high-density lipoprotein (HDL) may play an anti-atherogenic role as an antioxidant and inhibit the oxidative modification of low-density lipoprotein (LDL). The antioxidant activity of HDL has been proposed to be associated with several HDL-bound proteins. We have purified one HDL-associated protein, lecithin:cholesterol acyltransferase (LCAT), to apparent homogeneity and have found that LCAT is not only capable of esterifying cholesterol in the plasma, but can also prevent the accumulation of oxidized lipids in LDL. Addition of pure human LCAT to LDL or palmitoyl-linoleoyl phosphatidylcholine/sodium cholate (PLPC) micelles inhibits the oxidation-dependent accumulation of both conjugated dienes and lipid hydroperoxides. LCAT also inhibits the increase of net negative charge that occurs during oxidation of LDL. LCAT has the ability to prevent spontaneous oxidation and Cu2+ and soybean lipoxygenase-catalyzed oxidation of lipids. The antioxidant activity of LCAT appears to be enzymatic, since the enzyme is active for up to 10 h in the presence of mild free-radical generators. The catalytic serine, residue 181, may mediate this activity and act as a reusable proton donor. Chemical modification of the active serine residue with diisopropylfluorophosphate completely inhibits the ability of LCAT to prevent lipid oxidation. Thus, in addition to its well-characterized phospholipase and acyltransferase activities, LCAT can also act as an antioxidant and prevent the accumulation of oxidized lipid in plasma lipoproteins. |
| A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a) Menke, J. G., K. L. Macnaul, et al. (2002), Endocrinology 143(7): 2548-58. Abstract: The liver X receptors, LXRalpha and LXRbeta, are members of the nuclear receptor superfamily. Originally identified as orphans, both receptor subtypes have since been shown to be activated by naturally occurring oxysterols. LXRalpha knockout mice fail to regulate cyp7a mRNA levels upon cholesterol feeding, implicating the role of this receptor in cholesterol homeostasis. LXR activation also induces the expression of the lipid pump involved in cholesterol efflux, the gene encoding ATP binding cassette protein A1 (ABCA1). Therefore, LXR is believed to be a sensor of cholesterol levels and a potential therapeutic target for atherosclerosis. Here we describe a synthetic molecule named F(3)MethylAA 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-(4,5)-isoxazolyl)propylthio)- phenyl acetic acid that is more potent than 22(R)-hydroxycholesterol in LXR in vitro assays. F(3)MethylAA is capable not only of inducing ABCA1 mRNA levels, but also increasing cholesterol efflux from THP-1 macrophages. In rat hepatocytes, F(3)MethylAA induced cyp7a mRNA, confirming conclusions from the knockout mouse studies. Furthermore, in rat in vivo studies, F(3)MethylAA induced liver cyp7a mRNA and enzyme activity. A critical species difference is also reported in that neither F(3)MethylAA nor 22(R)-hydroxycholesterol induced cyp7a in human primary hepatocytes. However, other LXR target genes, ABCA1, ABCG1, and SREBP1, were regulated. |
| A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression Kuvin, J. T., M. E. Ramet, et al. (2002), Am Heart J 144(1): 165-72. Abstract: BACKGROUND: Low levels of high-density lipoprotein (HDL) cholesterol increase the risk of coronary artery disease (CAD), and recent clinical studies suggest that interventions in low-HDL patients are beneficial. The purpose of this study was to examine the effect of increased HDL levels on endothelium-dependent vasodilation. METHODS: We studied patients with CAD with a low-density lipoprotein (LDL) level of <100 mg/dL. Patients with an HDL level of < or =36 mg/dL were treated with niacin (n = 11), and patients with an HDL level of >36 mg/dL were followed as controls (n = 10). Baseline and 3-month follow-up studies of flow-mediated dilation (FMD) and blood lipid levels were obtained. RESULTS: HDL levels increased from 30.1 +/- 1.2 to 40.5 +/- 1.2 mg/dL in the niacin-treated patients (P <.001) but remained unchanged in the control patients. At baseline, FMD was impaired in both the treated (6.5% +/- 1%) and the control (7.3% +/- 1%) patients compared with 10 healthy subjects (16% +/- 2%, P <.01). After 3 months, FMD improved in the niacin-treated patients (11.8% +/- 1%, P =.001) but remained unchanged in the control patients (6.2% +/- 1%). Exposure of cultured human vascular endothelial cells to HDL in vitro enhanced expression of endothelial nitric oxide synthase (eNOS), as shown by immunoblotting. CONCLUSIONS: In patients with CAD and well-controlled LDL levels, elevation of HDL with niacin improves endothelial function. HDL increases eNOS protein expression in cultured vascular endothelial cells. Taken together, these observations suggest that HDL-mediated increases in eNOS expression may contribute to the observed enhancement in vasorelaxation and thus support a previously unrecognized mechanism for the beneficial cardiovascular effects of HDL. |
| A novel mutant, ApoA-I nichinan (Glu235-->0), is associated with low HDL cholesterol levels and decreased cholesterol efflux from cells Han, H., J. Sasaki, et al. (1999), Arterioscler Thromb Vasc Biol 19(6): 1447-55. Abstract: A novel variant of apolipoprotein (apo) A-I associated with low high density lipoprotein (HDL) cholesterolemia has been identified in a Japanese family during screening for apoA-I variants by isoelectric focusing (IEF) gel analysis. ApoA-I (Glu235-->0) Nichinan was caused by a 3-bp deletion of nucleotides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma concentrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. There were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, plasma lecithin:cholesterol acyltransferase activity was normal. Functional consequences of the mutation were examined by expressing the mutated and wild-type proapoA-I cDNAs in Escherichia coli. Cholesterol efflux to recombinant proapoA-I Nichinan from mouse peritoneal macrophages loaded with 3Hcholesterol-labeled acetylated low density lipoprotein was decreased by 54% when compared that of normal recombinant proapoA-I. In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu235-->0) Nichinan induced a critical structural change in the carboxyl-terminal domain of apoA-I for cellular cholesterol efflux and increased the catabolism of apoA-I, resulting in low HDL cholesterol levels. |
| A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb(3)), eliminates the cholesterol requirement for high affinity gp120/Gb(3) interaction Mahfoud, R., M. Mylvaganam, et al. (2002), J Lipid Res 43(10): 1670-9. Abstract: We have analyzed the interaction of adamantyl Gb(3) (adaGb(3)), a semi-synthetic soluble analog of Gb(3), with HIV-1 surface envelope glycoprotein gp120. In this analog, which was orginally designed to inhibit verotoxin binding to its glycolipid receptor, Gb(3), the fatty acid chain is replaced with a rigid globular hydrocarbon frame (adamantane). Despite its solubility, adaGb(3) forms monolayers at an air-water interface. Compression isotherms of such monolayers demonstrated that the adamantane substitution resulted in a larger minimum molecular area and a more rigid, less compressible film than Gb(3). Insertion of gp120 into adaGb(3) monolayers was exponential whereas the gp120/Gb(3) interaction curve was sigmoidal with a lag phase of 40 min. Adding cholesterol into authentic Gb(3) monolayers abrogated the lag phase and increased the initial rate of interaction with gp120. This effect of cholesterol was not observed with phosphatidylcholine or sphingomyelin. In addition, verotoxin-bound adaGb(3) or Gb(3) plus cholesterol was recovered in fractions of comparable low density after ultracentrifugation through sucrose-density gradients in the presence of Triton X-100. The unique biological and physico-chemical properties of adaGb(3) suggest that this analog may be a potent soluble mimic of Gb(3), providing a novel concept for developing GSL-derived viral fusion inhibitors. |
| A novel TC deletion resulting in Pro(260)-->Stop in the human LCAT gene is associated with a dominant effect on HDL-cholesterol Kasid, A., J. Rhyne, et al. (2001), Atherosclerosis 156(1): 127-32. Abstract: Human lecithin:cholesterol acyltransferase (LCAT) plays a key role in the biogenesis of circulating high-density lipoprotein-cholesterol (HDL-C) and reverse cholesterol efflux. We investigated the molecular defect in the LCAT gene in a family with low levels of HDL-C. The proband, a 53-year-old woman from Oklahoma City, had a HDL-C level of 0.21 mmol/l. The LCAT activity in the proband was 5 nmol/ml/h and cholesterol esterification rate was 54.2 nmol/ml/h, consistent with LCAT deficiency. Analysis of polymerase chain reaction (PCR) amplified subgenomic fragments of LCAT DNA on polyacrylamide gels revealed heteroduplex bands in the proband and three other affected individuals in exon 6. DNA sequence analyses of the proband's LCAT gene identified a 2 base pair deletion (TC) (base pairs 4544-4545, corresponding to amino acid 255) in the heteroduplex allele, thereby converting Pro(260) to a premature stop codon and a predicted truncated protein of 260 amino acids. This is approximately 60% of the length of the normal translated protein. The heterozygous individuals also revealed significant reduction in apolipoprotein A-1 levels compared with the unaffected family members (n=4). The marked reduction in HDL-C in the proband and sibling suggests a dominant effect of this mutation on HDL-C levels. Furthermore, because the deletion results in a heterozygous allele that can be detected by a simple PCR reaction and polyacrylamide gel-size fractionation, it may be possible to rapidly screen susceptible individuals for the presence of this mutation. |
| A novel telephone-based system for management of secondary prevention to a low-density lipoprotein cholesterol < or = 100 mg/dl Robinson, J. G., C. Conroy, et al. (2000), Am J Cardiol 85(3): 305-8. Abstract: Unfortunately, lipid-lowering drug therapy remains underutilized in clinical practice, and few secondary prevention patients achieve the low-density lipoprotein (LDL) cholesterol level (< or = 100 mg/dl) recommended by the National Cholesterol Education Program. To improve patient management, a telephone-based computerized system primarily managed by dietitians was implemented in one of our cardiology clinics. Lipid results from all lipid and cardiology referrals and patients admitted to the cardiology service at 1 hospital are managed through this system. Patients are contacted via computer-generated postcards and the dietitians every 3 to 6 months. At baseline (September 1, 1994, through August 31, 1995; n = 1,969), 34% and 66% had LDL cholesterol < or = 100 and < or = 130 mg/dl, respectively. By September 1, 1997, to August 31, 1998 (n = 2,827), the proportion of patients with LDL cholesterol < or = 100 mg/dl had increased to 61%, and 89% had LDL cholesterol < or = 130 mg/dl. Statin use increased from 47% to 85% of patients. By 1997 to 1998, 74% and 40% of patients received statin doses that would, on average, produce a 34% and 41% reduction in LDL cholesterol, respectively. Whether a patient had LDL cholesterol < or = 100 mg/dl was not predicted by patient characteristics, drugs given, or by medication insurance coverage. |
| A novel test for the measurement of skin cholesterol Zawydiwski, R., D. L. Sprecher, et al. (2001), Clin Chem 47(7): 1302-4. |