| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Novel acyl-CoA:cholesterol acyltransferase inhibitors. Synthesis and biological activity of 3-quinolylurea derivatives Tawada, H., M. Harcourt, et al. (1994), J Med Chem 37(13): 2079-84. Abstract: A series of 3-quinolylurea derivatives (1) was synthesized and evaluated for acyl-CoA:cholesterol acyltransferase (ACAT) inhibitory activity. For in vitro studies, the most potent inhibitory activity was found in derivatives having substituents at the 6,7- or 6,8-positions and an ortho-substituted phenyl group at the 4-position of quinoline ring. The 2,4-difluorophenyl group appeared to be the optimum N'-substituent of the urea moiety. The IC50 values of compounds 52-54 and 59 were in the nanomolar order. Plasma cholesterol-lowering activity of compounds 50, 52, and 54 was observed at less than 1 mg/kg/day in cholesterol-fed rats. Compound 52 was also hypocholesterolemic in hamsters fed a diet without loading cholesterol. |
| Novel biodegradable cholesterol-modified polyrotaxane hydrogels for cartilage regeneration Tachaboonyakiat, W., T. Furubayashi, et al. (2004), J Biomater Sci Polym Ed 15(11): 1389-404. Abstract: Cholesterol was introduced to a hydrolyzable polyrotaxane (PRx), not only to improve cell proliferation and glycosaminoglycan (GAG) production, but also to control the degradation rate of the hydrogels. The cholesterol was introduced to hydrolyzable PRx species by threading many alpha-cyclodextrins (alpha-CDs) on a poly(ethylene glycol) (PEG) chain having hydrolyzable ester linkages at the terminals; the PRx species were then cross-linked with other PEGs to prepare cholesterol-modified PRx hydrogels. The degree of cholesterol substitution was varied in the range of 1-25%. These hydrogels were examined to clarify the effect of cholesterol groups on mechanical properties, erosion time and chondrocyte proliferation. Highly porous biodegradable cholesterol-modified PRx hydrogels were fabricated using a combination of potassium hydrogen carbonate (as an effervescent salt) and citric acid. This fabrication process enabled the homogeneous expansion of pores within the polymer matrices, leading to well-interconnected macroporous hydrogels with a mean pore size of around 200-400 microm, ideal for high-density chondrocyte seeding. Time to complete degradation of the hydrogels was shortened by increasing the degree of substitution due to the aggregation of alpha-CDs through hydrophobic interaction of cholesterol groups. The presence of approx. 10% cholesterol improved the chondrocyte proliferation and GAG production. The modification of cholesterols to PRx is a good approach for creating new biodegradable hydrogels in terms of chondrocyte culture and controlling degradation time of the hydrogels. |
| Novel biosynthetic pathway of castasterone from cholesterol in tomato Kim, T. W., S. C. Chang, et al. (2004), Plant Physiol 135(3): 1231-42. Abstract: Endogenous brassinosteroids (BRs) in tomato (Lycopersicon esculentum) seedlings are known to be composed of C27- and C28-BRs. The biosynthetic pathways of C27-BRs were examined using a cell-free enzyme solution prepared from tomato seedlings that yielded the biosynthetic sequences cholesterol --> cholestanol and 6-deoxo-28-norteasterone <--> 6-deoxo-28-nor-3-dehydroteasterone <--> 6-deoxo-28-nortyphasterol --> 6-deoxo-28-norcastasterone --> 28-norcastasterone (28-norCS). Arabidopsis CYP85A1 that was heterologously expressed in yeast mediated the conversion of 6-deoxo-28-norCS to 28-norCS. The same reaction was catalyzed by an enzyme solution from wild-type tomato but not by an extract derived from a tomato dwarf mutant with a defect in CYP85. Furthermore, exogenously applied 28-norCS restored the abnormal growth of the dwarf mutant. These findings indicate that the C-6 oxidation of 6-deoxo-28-norCS to 28-norCS in tomato seedlings is catalyzed by CYP85, just as in the conversion of 6-deoxoCS to CS. Additionally, the cell-free solution also catalyzed the C-24 methylation of 28-norCS to CS in the presence of NADPH and S-adenosylmethionine (SAM), a reaction that was clearly retarded in the absence of NADPH and SAM. Thus it seems that C27-BRs, in addition to C28-BRs, are important in the production of more active C28-BRs and CS, where a SAM-dependent sterol methyltransferase appears to biosynthetically connect C27-BRs to C28-BRs. Moreover, the tomato cell-free solution converted CS to 26-norCS and 2H6CS to 2H328-norCS, suggesting that C-28 demethylation is an artifact due to an isotope effect. Although previous feeding experiments employing 2H6CS suggested that 28-norCS was synthesized from CS in certain plant species, this is not supported in planta. Altogether, this study demonstrated for the first time, to our knowledge, that 28-norCS is not synthesized from CS but from cholesterol. In addition, CS and 2H6CS were not converted into BL and 2H6BL, respectively, confirming an earlier finding that the active BR in tomato seedlings is not BL but CS. In conclusion, the biosynthesis of 28-norBRs appears to play a physiologically important role in maintaining homeostatic levels of CS in tomato seedlings. |
| Novel branched poly(ethylenimine)-cholesterol water-soluble lipopolymers for gene delivery Wang, D. A., A. S. Narang, et al. (2002), Biomacromolecules 3(6): 1197-207. Abstract: A novel water-soluble lipopolymer was synthesized by linking cholesteryl chloroformate to the secondary amino groups of branched poly(ethylenimine) (PEI) of 1,800 and 10,000 Da. Conjugation through PEI secondary amines gives this newly synthesized lipopolymer (abbreviated as PEI-Chol) special advantage over our previously synthesized lipopolymers, which utilized the primary amino groups for conjugation, as the primary amino groups have a significant role in DNA condensation. Also, significantly, only one cholesterol molecule was grafted onto each PEI molecule (confirmed by (1)H NMR and MALDI-TOF mass spectrometry), leaving enough space for the steric interactions of the PEI's primary amines with the DNA. The PEI-Chol lipopolymer was characterized for the critical micellar concentration (cmc), buffer capacity, DNA condensation (by band retardation and circular dichroism), in vitro transfection efficiency, and cell viability. The cmcs of PEI-Chol 1,800 and PEI-Chol 10,000 were 496.6 and 1,330.5 microg/mL, respectively. The acid-base titration indicated high buffering capacity of the polymers around the pH range of 5-7, which indicated their potential for buffering in the acidic pH environment of the endosomes. The band retardation studies indicated that efficient condensation of the plasmid DNA could be achieved using these lipopolymers. The circular dichroism spectra indicated a change in DNA conformation and adoption of lower energy state upon condensation with these lipopolymers when an N/P ratio of 2.5/1 or above was formulated. The mean particle size of these complexes was in the range 110-205 nm, except for the complexes prepared using PEI of 1,800 Da, which had a mean particle size of 384 +/- 300 nm. The zeta potential of DNA complexes prepared using PEI-Chol 1,800, PEI-Chol 10,000 and PEI of 1,800, 10,000, and 25,000 Da at an N/P ratio of 15/1 was in the range 23-30 mV and was dependent on the N/P ratios. The in vitro transfection of PEI-Chol/pCMS-EGFP complexes in Jurkat cells showed high levels of expressed Green Fluorescent Protein (GFP) with little toxicity as determined by flow cytometry. These novel water-soluble lipopolymers provided good transfection efficiency with other desirable characteristics such as water solubility, free primary amino groups for efficient DNA condensation and high buffer capacity that indicated the possibility of efficient endosomal release. |
| Novel effects of histamine on lipoprotein metabolism: suppression of hepatic low density lipoprotein receptor expression and reduction of plasma high density lipoprotein cholesterol in the rat Liao, W., M. Rudling, et al. (1997), Endocrinology 138(5): 1863-70. Abstract: Histamine has been shown to be involved in atherosclerosis and coronary heart disease. Little information is available regarding the effects of histamine on lipoprotein metabolism. In the current study, we investigated the effects of histamine on the expression of hepatic low density lipoprotein (LDL) receptors and on plasma lipoproteins in the rat. Injection of compound 48/80 (C48/80, a histamine releaser) or histamine reduced hepatic LDL receptor expression, but not LDL receptor messenger RNA levels. Oral administration of polymyxin B (an antiendotoxin antibiotic and a histamine releaser) before the injection of C48/80 or histamine did not attenuate their effects. Polymyxin B itself had effects similar to those of C48/80 and histamine on LDL receptors. These results suggest that the effects of histamine are not mediated by the induction of gut-derived endotoxemia. Histamine H2 agonists (dimaprit and impromidine), but not H1 agonists (2-methylhistamine and 2-thiazolylethylamine), also reduced hepatic LDL receptor expression. The suppressive effect of C48/80 on hepatic LDL receptor expression was not attenuated by either the H1 antagonist (chlorpheniramine) or the H2 antagonist (cimetidine). Administration of C48/80 also reduced plasma high density lipoprotein (HDL) cholesterol. The H1 antagonist (chlorpheniramine), but not the H2 antagonist (cimetidine), almost completely reversed the effect of C48/80 on plasma HDL cholesterol. In conclusion, histamine suppresses hepatic LDL receptor expression via a non-H1 receptor-mediated pathway, and histamine reduces plasma HDL cholesterol via an H1 receptor-mediated pathway. |
| Novel effects of the acyl-coenzyme A:Cholesterol acyltransferase inhibitor 58-035 on foam cell development in primary human monocyte-derived macrophages Rodriguez, A., P. S. Bachorik, et al. (1999), Arterioscler Thromb Vasc Biol 19(9): 2199-206. Abstract: We examined the effect of acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on intracellular cholesterol stores in primary human monocyte-derived macrophages (HMMs) during foam cell formation. HMMs were exposed to acetylated low density lipoprotein (acLDL, 500 microg protein per mL) with or without 58-035 (1 to 10 microg/mL) or CI-976 (2 microg/mL) for 2 to 48 hours. Total cholesterol (TC) and esterified cholesterol (EC) mass was significantly lower while unesterified cholesterol (UC) increased slightly in cells incubated with acLDL plus ACAT inhibitors. Sterol mass was also measured in cells coincubated with acLDL (500 microg protein per mL) with or without 58-035 (2 microg/mL), high density lipoprotein (HDL, 400 microg protein per mL), or HDL+58-035 for 48 hours. TC and EC were 23% and 55% lower, respectively (P<0.0004), while UC was 11% higher (P<0.04) in cells incubated with acLDL plus 58-035. In contrast, coincubation with HDL alone did not significantly affect TC, EC, or UC mass compared with acLDL alone. The effect of 58-035 could not be explained by cytotoxicity, because adenine release, secreted lactate dehydrogenase, glucose utilization, and cell protein were similar in cells exposed to acLDL regardless of the presence of 58-035. We investigated several potential mechanisms for the decreased TC mass, including increased UC efflux and decreased acLDL binding and uptake. Efflux was measured in cells exposed to 1,2-(3)Hcholesteryl oleate-labeled acLDL, unlabeled control acLDL, and native untreated acLDL (500 microg protein per mL) with or without 58-035 (5 microg/mL) for 24 or 48 hours. UC efflux increased in a time-dependent manner from cells exposed to acLDL plus 58-035 compared with cells exposed to acLDL alone (P<0. 04). High-affinity binding was measured in cells exposed to (125)I-acLDL (5 microg protein per mL) with or without excess unlabeled acLDL (100 or 500 microg protein per mL) for 4 hours at 4 degrees C. Specific acLDL binding, uptake, and total degradation were significantly lower when 58-035 was present during cholesterol enrichment compared with cells exposed to acLDL alone (P<0.001). Unlike the effects of ACAT inhibitors on foam cell formation in rodent macrophages, these compounds lowered TC accumulation in HMMs during foam cell formation by limiting the uptake of acLDL and enhancing UC efflux. They may offer promise as drug therapies for atherosclerosis. |
| Novel electrochemical device for the detection of cholesterol or glucose Cassidy, J. F., C. Clinton, et al. (1993), Analyst 118(4): 415-8. Abstract: A thin-layer twin-electrode electrochemical cell in which the working and auxiliary electrodes are facing each other and which contains the appropriate enzyme and a mediator was used for the determination of cholesterol or glucose. A steady-state diffusion-controlled response was obtained for cholesterol whereas for glucose the response was limited by diffusion and kinetics. Simulation of the system showed that a steady-state response is obtained, in the absence of kinetic complications, after a time of 0.01 d2/Ds, where d is the distance between the two electrodes and D is the diffusion coefficient of the mediator. Linear plots of steady-state current versus concentration were obtained for cholesterol and glucose. The results were compared with those expected theoretically and a thin-layer capillary fill device is proposed. |
| Novel high relaxivity colloidal particles based on the specific phase organisation of amphiphilic gadolinium chelates with cholesterol Glogard, C., G. Stensrud, et al. (2003), Int J Pharm 253(1-2): 39-48. Abstract: To obtain high T(1)-relaxivity colloidal particles with a simultaneously high loading of amphiphilic Gd-chelates, a novel drug dosage form based on the phase organisation of amphiphilic gadolinium chelates with cholesterol was developed.In order to find a formulation, which exhibit both high T(1)-relaxivity and gives small particles a D-optimal mixture design (experimental design) was applied. Gadolinium 1,4,7-tris(carboxymethyl)-10-(2-hydroxyhexadecyl)-1,4,7,10-tetraazacyclodo decane (Gd-HHD-DO3A) and cholesterol at approximately equimolar ratio proved to form thermodynamic stable disc-like colloidal particles as seen by cryo-electron micrographs. T(1)-relaxivity of these particles was typically around 20mM(-1)s(-1) and the size below 100 nm (photon correlation spectroscopy (PCS)). The particles do most probably not interact with blood components as no change in T(1)-relaxivity was observed when the particles were mixed with whole blood. The particles were stable at room temperature for at least 6 months. |
| Novel HPLC analysis of tocopherols, tocotrienols, and cholesterol in tissue Katsanidis, E. and P. B. Addis (1999), Free Radic Biol Med 27(11-12): 1137-40. Abstract: Tocopherols and tocotrienols are being increasingly recognized to have an important role in the prevention of atherosclerosis. It has been reported that they protect low-density lipoprotein (LDL) and tissues from oxidative stress and that tocotrienols can reduce plasma cholesterol levels. Two isocratic high-performance liquid chromatography (HPLC) methods for simultaneous analysis of tocopherols, tocotrienols, and cholesterol in muscle tissue were developed. Method A involves basic saponification of the sample, but causes losses of the gamma- and delta-homologs of vitamin E. Method B does not involve saponification, thereby protecting the more sensitive homologs. Both permit rapid analysis of multiple samples and neither requires specialized equipment. These methods may provide techniques useful in simultaneous assessment of oxidative stress status (OSS) and cholesterol levels. |
| Novel mutations that control the sphingolipid and cholesterol dependence of the Semliki Forest virus fusion protein Chatterjee, P. K., C. H. Eng, et al. (2002), J Virol 76(24): 12712-22. Abstract: The enveloped alphavirus Semliki Forest virus (SFV) infects cells via a membrane fusion reaction mediated by the E1 membrane protein. Efficient SFV-membrane fusion requires the presence of cholesterol and sphingolipid in the target membrane. Here we report on two mutants, srf-4 and srf-5, selected for growth in cholesterol-depleted cells. Like the previously isolated srf-3 mutant (E1 proline 226 to serine), the phenotypes of the srf-4 and srf-5 mutants were conferred by single-amino-acid changes in the E1 protein: leucine 44 to phenylalanine and valine 178 to alanine, respectively. Like srf-3, srf-4 and srf-5 show striking increases in the cholesterol independence of growth, infection, membrane fusion, and exit. Unexpectedly, and unlike srf-3, srf-4 and srf-5 showed highly efficient fusion with sphingolipid-free membranes in both lipid- and content-mixing assays. Both srf-4 and srf-5 formed E1 homotrimers of decreased stability compared to the homotrimers of the wild type and the srf-3 mutant. All three srf mutations lie in the same domain of E1, but the srf-4 and srf-5 mutations are spatially separated from srf-3. When expressed together, the three mutations could interact to produce increased sterol independence and to cause temperature-sensitive E1 transport. Thus, the srf-4 and srf-5 mutations identify novel regions of E1 that are distinct from the fusion peptide and srf-3 region and modulate the requirements for both sphingolipid and cholesterol in virus-membrane fusion. |
| Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels Blumenthal, J. B., R. E. Andersen, et al. (2002), Clin Genet 62(3): 196-202. Abstract: Neuropeptide Y (NPY) appears to play a critical role in the integration of appetite and energy expenditure through NPY Y1 and Y5 receptor subtypes. Moreover, the NPY Y1 receptor is highly expressed on human adipocytes, where it inhibits lipolysis. The genes encoding these receptors are transcribed co-ordinately in opposite directions from a common promoter in a region of chromosome 4 that has been previously linked to triglyceride and small low-density lipoprotein (LDL) particle concentration. Therefore, the purpose of this investigation was to examine the relationship between polymorphisms in the genes encoding NPY Y1 and Y5 and the development of obesity and dyslipidemia. We screened the promoter and coding regions and identified four polymorphic variants. One of these, a cytosine to thymine (C-->T) substitution in the untranslated region between the genes for NPY Y1 and Y5 (allele frequency 0.11), was significantly associated with both lower fasting triglyceride level (152 vs 125 mg/dl), and higher high-density lipoprotein (HDL) concentrations (49 vs 45 mg/dl) (p < 0.01) in 306 obese subjects. Given the stimulatory effect of NPY on adipocyte lipoprotein lipase (LPL) activity, and the lack of association of other polymorphisms with serum lipid levels, we hypothesize that this is a gain-in-function polymorphism. |
| Novel pathways for elimination of cholesterol by extrahepatic formation of side-chain oxidized oxysterols Diczfalusy, U., E. Lund, et al. (1996), Scand J Clin Lab Invest Suppl 226: 9-17. Abstract: Recently, we described a new pathway whereby peripheral cells can eliminate intracellular cholesterol by conversion into the more polar oxysterols 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid. The latter steroids are easily excreted from the cells and transported to the liver for conversion into bile acids. Our attempts to evaluate the importance of this new mechanism are reviewed here and also our investigations on the possible presence of additional similar pathways for removal of extrahepatic cholesterol. Human alveolar macrophages in culture were shown to have a high capacity to convert cholesterol into 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid and to excrete these steroids into the culture medium. Treatment of the macrophages with cyclosporin A, an inhibitor of sterol 27-hydroxylase, reduced the excretion of the 27-hydroxylated products by more than 90%, with a concomitant accumulation of intracellular cholesterol. The quantitative importance of the mechanism in relation to reverse cholesterol transport was investigated in 14C-cholesterol labelled macrophages exposed to HDL. At very low concentrations of HDL, possibly similar to those present in tissues, the two pathways were about equally effective. At optimal concentrations of HDL, however, reverse cholesterol transport was about 10-fold more effective than the sterol 27-hydroxylase pathway. The net uptake of 27-oxygenated steroids by the liver was measured in volunteers by comparison of the levels in the hepatic vein with those in a peripheral artery. Approximately 20 mg of 27-oxygenated oxysterols was taken up by the liver during 24 hours. Quantitative conversion of these oxysterols into bile acids would correspond to 4% of the total bile acid formation. It is evident that this new pathway contributes significantly to cholesterol elimination. The possibility that the sterol 27-hydroxylase pathway is of importance for cholesterol homeostasis in the brain was investigated by measuring oxysterols in the internal jugular vein and in an artery of healthy volunteers. There was no net flux of 27-hydroxycholesterol from the brain into the circulation. There was, however, a significant flux of 24-hydroxycholesterol, corresponding to elimination of about 4 mg cholesterol/24 hours. This flux is higher than the estimated rate of synthesis of cholesterol in the human brain. To summarize, we have demonstrated two mechanisms for cholesterol elimination from extrahepatic cells by specific oxygenases capable of oxidizing the steroid side-chain. The efficiency of these mechanisms is based on the fact that side-chain hydroxylated cholesterol species are both translocated through lipophilic membranes and converted into bile acids at a much faster rate than cholesterol itself. The importance of the sterol 27-hydroxylase-mediated mechanism is illustrated by the fact that patients who lack this enzyme develop xanthomas and premature atherosclerosis in spite of normal levels of circulating cholesterol. |
| Novel polypyrimidine variation (IVS46: del T -39.-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease Hong, S. H., J. Rhyne, et al. (2003), Circ Res 93(10): 1006-12. Abstract: Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39.-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39.-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain. |
| Novel properties of cholesterol-dioleoylphosphatidylcholine mixtures Epand, R. M., D. W. Hughes, et al. (2003), Biochim Biophys Acta 1616(2): 196-208. Abstract: We have studied the properties of mixtures of cholesterol with dioleoylphosphatidylcholine (DOPC), and with several other phospholipids, including 1-stearoyl-2-oleoylphosphatidylcholine (SOPC) and dioleoleoylphosphatidylserine (DOPS), as a function of cholesterol molar fraction and of temperature. Mixtures of DOPC with a cholesterol molar fraction of 0.4 or greater display polymorphic behavior. This polymorphism includes the formation of structures that give rise to isotropic peaks in 31P NMR at cholesterol molar fractions between 0.4 and 0.6, dependent on the thermal history of the sample. Cryo-electron microscopy studies demonstrate the formation of small globular aggregates that would contribute to a narrowing of the 31P NMR powder pattern.At molar fraction cholesterol 0.6 and higher and at temperatures above 70 degrees C, the mixtures with DOPC convert to the hexagonal phase. Lipid polymorphism is accompanied by the phase separation of cholesterol crystals in the anhydrous form and/or the monohydrate form. The crystals that are formed have substantially altered kinetics of hydration and dehydration, compared with both pure cholesterol monohydrate crystals and with crystals formed in the presence of the other phospholipids that do not form the hexagonal phase in the presence of cholesterol. This fact demonstrates that these cholesterol crystals are in intimate contact with the DOPC phospholipid and are not present as morphologically separate structures. |
| Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice Maxwell, K. N., R. E. Soccio, et al. (2003), J Lipid Res 44(11): 2109-19. Abstract: High-cholesterol diets elicit changes in gene expression via such transcription factors as sterol-regulatory element binding proteins (SREBPs) and liver X receptors (LXRs). We used Affymetrix microarrays to identify genes in mouse liver regulated by dietary cholesterol (0.0% vs. 0.5% cholesterol wt/wt). Three independent experiments were performed, and data were analyzed with Affymetrix Microarray Suite and ANOVA statistical software. There were 69 unique Unigene clusters consistently regulated by dietary cholesterol (37 downregulated and 32 upregulated). The array results were confirmed by quantitative RT-PCR (Q-PCR) for seven of nine downregulated genes and five of six upregulated genes. A time course of dietary cholesterol feeding over 1 week revealed different temporal patterns of gene regulation for these confirmed genes. Six downregulated genes were examined in transgenic mice overexpressing truncated nuclear forms of SREBP-1a and SREBP-2, and all were induced in these mice. A second microarray analysis of mice treated with the LXR agonist TO901317 confirmed that 13 of the 32 cholesterol upregulated genes were also LXR-activated. This array result was confirmed by Q-PCR for three of three genes. In summary, these studies identified and confirmed six novel dietary cholesterol-regulated genes, three putative SREBP target genes (calcium/calmodulin-dependent protein kinase 1D, fatty acid binding protein 5, and proprotein convertase subtilisin/kexin 9), and three putative LXR target genes (a disintegrin and metalloprotease domain 11, apoptosis-inhibitory 6, and F-box-only protein 3). |
| Novel risk factors for atherosclerosis. A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a) and cholesterol as predictors of peripheral arteriopathy Iacoviello, L., M. B. Donati, et al. (2001), Ital Heart J Suppl 2(9): 1031-3. |
| Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease Ridker, P. M., M. J. Stampfer, et al. (2001), Jama 285(19): 2481-5. Abstract: CONTEXT: Several novel risk factors for atherosclerosis have recently been proposed, but few comparative data exist to guide clinical use of these emerging biomarkers. OBJECTIVE: To compare the predictive value of 11 lipid and nonlipid biomarkers as risk factors for development of symptomatic peripheral arterial disease (PAD). DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study using plasma samples collected at baseline from a prospective cohort of 14 916 initially healthy US male physicians aged 40 to 84 years, of whom 140 subsequently developed symptomatic PAD (cases); 140 age- and smoking status-matched men who remained free of vascular disease during an average 9-year follow-up period were randomly selected as controls. MAIN OUTCOME MEASURE: Incident PAD, as determined by baseline total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol-HDL-C ratio, triglycerides, homocysteine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoproteins (apo) A-I and B-100. RESULTS: In univariate analyses, plasma levels of total cholesterol (P<.001), LDL-C (P =.001), triglycerides (P =.001), apo B-100 (P =.001), fibrinogen (P =.02), CRP (P =.006), and the total cholesterol-HDL-C ratio (P<.001) were all significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P =.009) and apo A-I (P =.05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P =.40) and homocysteine (P =.90) were observed. In multivariable analyses, the total cholesterol-HDL-C ratio was the strongest lipid predictor of risk (relative risk RR for those in the highest vs lowest quartile, 3.9; 95% confidence interval CI, 1.7-8.6), while CRP was the strongest nonlipid predictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In assessing joint effects, addition of CRP to standard lipid screening significantly improved risk prediction models based on lipid screening alone (P<.001). CONCLUSIONS: Of 11 atherothrombotic biomarkers assessed at baseline, the total cholesterol-HDL-C ratio and CRP were the strongest independent predictors of development of peripheral arterial disease. C-reactive protein provided additive prognostic information over standard lipid measures. |
| Novel signaling stimulated by arsenite increases cholesterol metabolism through increases in unphosphorylated steroidogenic acute regulatory (StAR) protein Zhao, D., H. Xue, et al. (2005), Mol Cell Endocrinol 231(1-2): 95-107. Abstract: Cholesterol metabolism to pregnenolone is dependent on the steroidogenic acute regulatory protein (StAR), which activates mitochondrial transfer of cholesterol to cytochrome CYP450scc. In mouse Y-1 adrenal cells and testis MA10 cells stimulation by 8-Bromo-cAMP (Br-cAMP) is augmented by a novel signaling initiated by low concentrations of arsenite (3-20 microM) and anisomycin (0.2 microM), a more selective stress agent. Each elevated StAR mRNA (three-fold after 6 h treatment) even with simultaneous stimulation by Br-cAMP. Arsenite produced parallel increases in StAR protein expression and cholesterol metabolism, but not for P450scc-mediated metabolism of 20alpha-hydroxycholesterol. Although arsenite and anisomycin each stimulated the phosphorylation of p38, the p38 inhibitor SB203580 (SB) produced additive increases in StAR expression. Cholesterol metabolism increased in parallel but without the increased StAR protein phosphorylation produced by Br-cAMP. Arsenite and anisomycin each elevated StAR mRNA but preferentially increased the 3.5 kb form relative to the 1.6 kb form. Arsenite and anisomycin each enhanced the stability of the more labile 3.5 kb mRNA which contains AU-rich elements that control mRNA stability. Although there were increases in both forms of StAR mRNA, arsenite did not stimulate a StAR promoter-reporter that exhibited a typical three-fold response to Br-cAMP. Arsenite and anisomycin may therefore activate a novel SB-independent MAP kinase which in part increases StAR expression through stabilizing the 3.5 kb mRNA but which may also activate a mechanism that by-passes transcription factors detected by the reporter. SB stimulation, which was completely blocked by a MEK inhibitor, was also selective towards the 3.5 kb StAR mRNA suggesting a second pathway for mRNA stabilization. These activations contrast with inhibition of StAR expression by arsenite at higher concentrations or longer incubation times. |
| Novel sterol 7 alpha-hydroxylase(s) active towards not cholesterol but side-chain oxygenated steroids in liver microsomes Shoda, J., N. Tanaka, et al. (1993), Gastroenterol Jpn 28(3): 438. |
| Novel sterol 7 alpha-hydroxylase(s), microsomal 27-hydroxycholesterol 7 alpha-hydroxylase, in cholesterol gallstone disease and its etiological significance Shoda, J., B. F. He, et al. (1994), J Gastroenterol 29(2): 241. |