| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Functional and morphological changes in the cochlea of cholesterol fed guinea pigs Kashiwado, I., Y. Hattori, et al. (1994), Nippon Ika Daigaku Zasshi 61(4): 321-9. Abstract: Although sensory neural hearing loss stemming from hypercholesterolemia has received attention in recent years, no information is available about inner ear injuries resulting from this condition. In this study, we prepared guinea pig models at hypercholesterolemia and observed the inner ear with a transmission electron microscope, and also investigated the effect of vitamin E (Vit. E) on these injuries. One hundred and thirty-nine white male Hartley guinea pigs weighing a mean of 250 g each were divided into three groups. Group A consisted of the control animals, which were fed by a stock diet. Group B animals were fed by a hyperlipid diet (2.5% cholesterol, 0.25% cholic acid, and 7.5% cattle fat). Group C animals were fed by a Vit. E-added (50 units/100 g) hyperlipid diet. All the animals were sacrificed either one, two or three months after treatment and the cochlea duct vasculature, cochleal nerve fiber under spiral limbus, stria vascularis and inner hair cell and outer hair cell of Corti's organ was observed with a transmission electron microscope. Cholesterol, triglyceride, and TBARS values were concurrently measured in the serum. Auditory threshold was measured by auditory brain stem response (ABR). In groups B and C, cholesterol and triglyceride levels remained high. The TBARS level elevated in group B but remained unchanged in groups A and C. In groups B and C, the threshold of ABR increased mildly. The cholesterol load led to injuries in the endothelium of the vasculature dominating the cochlea.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Functional expression of a cDNA to human acyl-coenzyme A:cholesterol acyltransferase in yeast. Species-dependent substrate specificity and inhibitor sensitivity Yang, H., D. Cromley, et al. (1997), J Biol Chem 272(7): 3980-5. Abstract: We have identified two yeast genes with similarity to a human cDNA encoding acyl-coenzyme A:cholesterol acyltransferase (ACAT). Deletion of both yeast genes results in a viable cell with undetectable esterified sterol (Yang, H., Bard, M., Bruner, D. A., Gleeson, A., Deckelbaum, R. J., Aljinovic, G., Pohl, T., Rothstein, R., and Sturley, S. L. (1996) Science 272, 1353-1356). Here, we expressed the human cDNA in the yeast double mutant, resulting in high level production of ACAT protein, but low in vivo esterification of ergosterol, the predominant yeast sterol. The activity of the human enzyme was increased by incubation of these cells with 25-hydroxy, cholesterol, an established positive regulator of mammalian sterol esterification. In contrast, the yeast enzymes were unaffected by this reagent. In vitro microsomal assays indicated no sterol esterification in extracts from the double mutant. However, significant activity was detected from strains expressing human ACAT when cholesterol was equilibrated with the microsomal membranes. The human enzyme in yeast utilized cholesterol as the preferred sterol and was sensitive to competitive (S58035) and non-competitive (DuP 128) ACAT inhibitors. The yeast esterifying enzymes exhibited a diminished sterol substrate preference and were sensitive only to S58035. Human ACAT had a broad acyl-CoA substrate specificity, the other substrate for this reaction. By contrast, the yeast enzymes had a marked preference for specific acyl-CoAs, particularly unsaturated C18 forms. These results confirm the yeast genes as functional homologs of the human gene and demonstrate that the enzymes confer substrate specificity to the esterification reaction in both organisms. |
| Functional foods nibble away at serum cholesterol concentrations Larkin, M. (2000), Lancet 355(9203): 555. |
| Functional foods: cholesterol-lowering benefits of plant sterols Thurnham, D. I. (1999), Br J Nutr 82(4): 255-6. |
| Functional foods: cholesterol-lowering benefits of plant sterols Weststrate, J. (2000), Br J Nutr 84(2): 253; discussion 253-4. |
| Functional lecithin:cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-II Marzal-Casacuberta, A., F. Blanco-Vaca, et al. (1996), J Biol Chem 271(12): 6720-8. Abstract: The concentration of high density lipoproteins (HDL) is inversely related to the risk of atherosclerosis. The two major protein components of HDL are apolipoprotein (apo) A-I and apoA-II. To study the role of apoA-II in lipoprotein metabolism and atherosclerosis, we have developed three lines of C57BL/6 transgenic mice expressing human apoA-II (lines 25.3, 21.5, and 11.1). Northern blot experiments showed that human apoA-II mRNA was present only in the liver of transgenic mice. SDS-polyacrylamide gel electrophoresis and Western blot analysis demonstrated a 17.4-kDa human apoA-II in the HDL fraction of the plasma of transgenic mice. After 3 months on a regular chow, the plasma concentrations of human apoA-II were 21 +/- 4 mg/dl in the 25.3 line, 51 +/- 6 mg/dl in the 21.5 line, and 74 +/- 4 mg/dl in the 11.1 line. The concentration of cholesterol in plasma was significantly lower in transgenic mice than in control mice because of a decrease in HDL cholesterol that was greatest in the line that expressed the most apoA-II (23 mg/dl in the 11.1 line versus 63 mg/dl in control mice). There was also a reduction in the plasma concentration of mouse apoA-I (32 +/- 2, 56 +/- 9, 91 +/- 7, and 111 +/- 2 mg/dl for lines 11.1, 21.5, 25.3, and control mice, respectively) that was inversely correlated with the amount of human apoA-II expressed. Additional changes in plasma lipid/lipoprotein profile noted in line 11.1 that expressed the highest level of human apoA-II include elevated triglyceride, increased proportion of total plasma, and HDL free cholesterol and a marked (>10-fold) reduction in mouse apoA-II. Total endogenous plasma lecithin:cholesterol acyltransferase (LCAT) activity was reduced to a level directly correlated with the degree of increased plasma human apoA-II in the transgenic lines. LCAT activity toward exogenous substrate was, however, only slightly decreased. The biochemical changes in the 11.1 line, which is markedly deficient in plasma apoA-I, an activator for LCAT, are reminiscent of those in patients with partial LCAT deficiency. Feeding the transgenic mice a high fat, high cholesterol diet maintained the mouse apoA-I concentration at a normal level (69 +/- 14 mg/dl in line 11.1 compared with 71 +/- 6 mg/dl in nontransgenic controls) and prevented the appearance of HDL deficiency. All this happened in the presence of a persistently high plasma human apoA-II (96 +/- 14 mg/dl). Paradoxical HDL elevation by high fat diets has been observed in humans and is reproduced in human apoA-II overexpressing transgenic mice but not in control mice. Finally, HDL size and morphology varied substantially in the three transgenic lines, indicating the importance of apoA-II concentration in the modulation of HDL formation. The LCAT and HDL deficiencies observed in this study indicate that apoA-II plays a dynamic role in the regulation of plasma HDL metabolism. |
| Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency Christiansen-Weber, T. A., J. R. Voland, et al. (2000), Am J Pathol 157(3): 1017-29. Abstract: Tangier disease (TD) and familial HDL deficiency (FHA) have recently been linked to mutations in the human ATP-binding cassette transporter 1 (hABCA1), a member of the ABC superfamily. Both diseases are characterized by the lowering or lack of high-density lipoprotein cholesterol (HDL-C) and low serum cholesterol. The murine ABCA1-/- phenotype corroborates the human TD linkage to ABCA1. Similar to TD in humans, HDL-C is virtually absent in ABCA1-/- mice accompanied by a reduction in serum cholesterol and lipid deposition in various tissues. In addition, the placenta of ABCA1-/- mice is malformed, resulting in severe embryo growth retardation, fetal loss, and neonatal death. The basis for these defects appears to be altered steroidogenesis, a direct result of the lack of HDL-C. By 6 months of age, ABCA1-/- animals develop membranoproliferative glomerulonephritis due to deposition of immunocomplexes followed by cardiomegaly with ventricular dilation and hypertrophy, ultimately succumbing to congestive heart failure. This murine model of TD will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them. |
| Functional properties in vitro of systemic small arteries from rabbits fed a cholesterol-rich diet for 12 weeks Simonsen, U., E. Ehrnrooth, et al. (1991), Clin Sci (Lond) 80(2): 119-29. Abstract: 1. Recent evidence has suggested that the impairment of endothelium-dependent cholinergic relaxation in vitro, which is seen in atherosclerotic large arteries of animals and man, could be part of a general deleterious effect to the endothelium of hypercholesterolaemia. 2. This possibility has been investigated in vitro by measuring the response to acetylcholine, sodium nitroprusside, 5-hydroxytryptamine and noradrenaline in segments of aorta and of femoral, mesenteric and cerebral small arteries (internal diameter approximately 200 microns) from control rabbits (n = 12) and from rabbits fed a 1% (w/w) cholesterol and 3% (w/w) coconut oil diet (n = 12) for 12 weeks. 3. Thoracic aorta segments from the control rabbits exhibited a maximal relaxation in response to acetylcholine of 64 +/- 11% compared with 10 +/- 5% (P less than 0.01) for thoracic segments from cholesterol-fed animals. Cerebral, femoral and mesenteric small arteries exposed to acetylcholine (10(-9)-10(-4) mol/l) relaxed to the same degree as arteries from control rabbits. The responses to sodium nitroprusside and bradykinin of the small arteries from the cholesterol-fed rabbits remained unaffected. 5-Hydroxytryptamine evoked comparable contractions in the small arteries, while the sensitivity to noradrenaline of the femoral small arteries was significantly decreased and the response of cerebral small arteries to noradrenaline in cholesterol-fed rabbits slightly increased compared with control rabbits. 4. Aorta from the cholesterol-fed rabbits had extensive atheromatous lesions. Morphological measurements and histological examination showed unchanged thickness and light microscopic appearance of intima and media of small arteries from cholesterol-fed animals compared with control animals. 5. The present study indicates that hypercholesterolaemia in this rabbit model is followed by atherosclerotic lesions and changed function of large arteries, but that both function and structure of systemic small arteries are largely unaffected. |
| Functional properties of cholesterol-removed whipping cream treated by beta-cyclodextrin Shim, S. Y., J. Ahn, et al. (2003), J Dairy Sci 86(9): 2767-72. Abstract: The present study was carried out to examine the changes in functional properties of cholesterol-removed whipping cream by beta-cyclodextrin (beta-CD) treatment. The cholesterol removal rate reached over 90% in cream before whipping in all conditions (different stirring time and speed) applied. The apparent viscosity of beta-CD treated cream after whipping increased with increased stirring time and speed. Comparatively, the overrun percentage reached to 150%, and foam instability was measured as 2.5 ml deformed cream with lower stirring time (10 min) and speed (400 rpm). The thiobarbituric acid value of cholesterol-removed whipping cream increased from 0.08 to 0.14 stored at 4 degrees C during 4 wk; however, no difference was found compared with that of control. Above results indicated that beta-CD treatment process for cholesterol removal did not show a profound adverse effect on functional properties of cream after whipping. |
| Functioning test for cholesterol turnover Inazu, A., J. Koizumi, et al. (1997), Nippon Rinsho 55 Suppl 1: 269-77. |
| Further evaluation of children with elevated total cholesterol on screening Franklin, F. A., Jr., B. Ho, et al. (1991), Ann N Y Acad Sci 623: 205-13. |
| Further evidence for low serum cholesterol and suicidal behaviour Sarchiapone, M., A. Roy, et al. (2000), J Affect Disord 61(1-2): 69-71. Abstract: OBJECTIVE: To examine for a relationship between serum cholesterol and suicidal behavior. METHODS: Patients admitted after an overdose (N=120) were compared with controls (N=120) for their serum cholesterol levels. RESULTS: Patients who had overdosed had significantly lower serum cholesterol levels than controls (mean+/-S.D. 171+/-31 vs. 196+/-30 mg/dl, P<0.0001). CONCLUSION: These results add to a grouping literature reporting that low serum cholesterol is associated with suicidal behavior. |
| Fushi tarazu factor-1 mRNA and protein is expressed in steroidogenic and cholesterol metabolising tissues during different life stages in Arctic char (Salvelinus alpinus) von Hofsten, J., J. Karlsson, et al. (2003), Gen Comp Endocrinol 132(1): 96-102. Abstract: Fushi tarazu factor-1 (FTZ-F1) genes belong to the nuclear receptor family 5A (NR5A). The distribution pattern of NR5A genes in teleosts suggests that they control functions separate to, or in addition to, those of other vertebrates. In mammals NR5A1 genes, including steroidogenic factor-1 (SF-1), are primarily involved in steroidogenesis. NR5A2 contain the alpha-fetoprotein transcription factor (FTF) genes, which protect mammalian embryos against maternal estrogens, and are involved in cholesterol transfer and metabolism. In this study we have analysed the expression of two Arctic char FTZ-F1 forms belonging to the NR5A2 group. The expression starts during early development and the transcripts are present in embryonic liver/pancreas and gonadal regions. The genes are up-regulated during embryogenesis as the embryo develops towards hatch, as shown by increased mRNA and protein levels. In adult Arctic char the FTZ-F1 forms are primarily located to tissues involved in steroidogenesis as well as cholesterol metabolism. Thus, a division of NR5A into SF-1 (NR5A1) and FTF (NR5A2) specific functions does not appear to have occurred in teleosts. |
| Fusion of influenza virus particles with liposomes: requirement for cholesterol and virus receptors to allow fusion with and lysis of neutral but not of negatively charged liposomes Nussbaum, O., R. Rott, et al. (1992), J Gen Virol 73 (Pt 11): 2831-7. Abstract: Influenza virus particles are able to fuse with liposomes composed of negatively charged or neutral phospholipids, as shown by using fluorochrome-labelled virions and fluorescence dequenching methods. Fusion with liposomes composed of only phosphatidylcholine (PC) was dependent on the presence of cholesterol (Chol), whereas fusion with liposomes containing negatively charged phospholipids, such as phosphatidylserine (PS), or of PC and phosphatidylethanolamine (PE) occurred in the absence of Chol. Fusion of influenza virions with PC:Chol liposomes was observed at pH 5.0, but not at pH 7.4, whereas a low degree of fusion with negatively charged liposomes or those containing PE was observed at pH 7.4. In addition, non-fusogenic influenza virions or HA0 influenza virions fused with PS- or PE-containing liposomes, especially at pH 5.0. Influenza virus particles were also able to induce the release of the fluorochrome calcein from negatively charged calcein-loaded liposomes at pH 5.0, as well as at pH 7.4, but failed to do so with PC:Chol liposomes. Lysis of PC:Chol by influenza virions was dependent on the presence of virus receptors, namely gangliosides (sialoglycolipids), and was observed only at pH 5.0. The results show that fusion of influenza virions with negatively charged or PE-containing liposomes does not reflect the biological activity of the virus needed for penetration and infection of living cells. On the other hand, fusion with PC:Chol liposomes is probably due to the activity of the viral fusion protein, the haemagglutinin glycoprotein. |
| Fusion of Semliki Forest virus with cholesterol-containing liposomes at low pH: a specific requirement for sphingolipids Wilschut, J., J. Corver, et al. (1995), Mol Membr Biol 12(1): 143-9. Abstract: Semliki Forest virus (SFV) utilizes a membrane fusion strategy to introduce its genome into the host cell. After binding to cell-surface receptors, virus particles are internalized through receptor-mediated endocytosis and directed to the endosomal cell compartment. Subsequently, triggered by the acid pH in the lumen of the endosomes, the viral envelope fuses with the endosomal membrane. As a result of this fusion reaction the viral RNA gains access to the cell cytosol. Low-pH-induced fusion of SFV, in model systems as well as in cells, has been demonstrated previously to be strictly dependent on the presence of cholesterol in the target membrane. In this paper, we show that fusion of SFV with cholesterol-containing liposomes depends on sphingomyelin (SM) or other sphingolipids in the target membrane, ceramide representing the sphingolipid minimally required for mediating the process. The action of the sphingolipid is confined to the actual fusion event, cholesterol being necessary and sufficient for low-pH-dependent binding of the virus to target membranes. The 3-hydroxyl group on the sphingosine backbone plays a key role in the SFV fusion reaction, since 3-deoxy-sphingomyelin does not support the process. This, and the remarkably low levels of sphingolipid required for half-maximal fusion (1-2 mol%), suggest that the sphingolipid does not play a structural role in SFV fusion, but rather acts as a cofactor, possibly through activation of the viral fusion protein. Domain formation between cholesterol and sphingolipid, although it may facilitate SFV fusion, is unlikely to play a crucial role in the process. |
| FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice Wittenburg, H., M. A. Lyons, et al. (2003), Gastroenterology 125(3): 868-81. Abstract: BACKGROUND & AIMS: Cholesterol gallstone formation is a complex genetic trait. To identify additional cholesterol gallstone susceptibility loci, we performed a quantitative trait locus analysis using an intercross of PERA/Ei and I/LnJ inbred strains of mice. METHODS: Mice of both sexes were examined for gallstone weight and evaluated according to a scoring system for the physical chemistry of cholelithiasis during feeding of a lithogenic diet. Intercross offspring were genotyped, and linkage analysis was performed by interval mapping. Differences in messenger RNA expression of positional candidate genes were determined using reverse-transcription and real-time polymerase chain reaction. RESULTS: We identified significant loci associated with gallstone weight on chromosomes 10 and 4, named Lith7 and Lith8, respectively (both susceptibility alleles conferred by strain I/LnJ). Positional candidate genes with higher expression in I/LnJ mice are Fxr (official symbol, Nr1h4), encoding the nuclear bile salt receptor, on chromosome 10 and Shp1 (official symbol, Nr0b2), encoding the small heterodimer partner 1, on chromosome 4. A significant locus associated with gallstone score on chromosome 17, named Lith9 (susceptibility allele conferred by strain PERA/Ei), colocalizes with the genes Abcg5 and Abcg8 that encode the canalicular cholesterol transporter. Higher hepatic messenger RNA expression of Abcg5 and Abcg8 in strain PERA/Ei correlates positively with higher biliary cholesterol levels. CONCLUSIONS: Our findings suggest a primary role of the nuclear bile salt receptor FXR and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenesis of cholesterol cholelithiasis in these strains of inbred mice. |
| FXR-mediated down-regulation of CYP7A1 dominates LXRalpha in long-term cholesterol-fed NZW rabbits Xu, G., H. Li, et al. (2003), J Lipid Res 44(10): 1956-62. Abstract: We investigated how cholesterol feeding regulates cholesterol 7alpha-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor alpha (LXRalpha) in New Zealand white rabbits. After 1 day of 2% cholesterol feeding, when the bile acid pool size had not expanded, mRNA levels of the FXR target genes short-heterodimer partner (SHP) and sterol 12alpha-hydroxylase (CYP8B) were unchanged, indicating that FXR activation remained constant. In contrast, the mRNA levels of the LXRalpha target genes ATP binding cassette transporter A1 (ABCA1) and cholesteryl ester transfer protein (CETP) increased 5-fold and 2.3-fold, respectively, associated with significant increases in hepatic concentrations of oxysterols. Activity and mRNA levels of CYP7A1 increased 2.4 times and 2.2 times, respectively. After 10 days of cholesterol feeding, the bile acid pool size increased nearly 2-fold. SHP mRNA levels increased 4.1-fold while CYP8B declined 64%. ABCA1 mRNA rose 8-fold and CETP mRNA remained elevated. Activity and mRNA of CYP7A1 decreased 60% and 90%, respectively. Feeding cholesterol for 1 day did not enlarge the ligand pool size or change FXR activation, while LXRalpha was activated highly secondary to increased hepatic oxysterols. As a result, CYP7A1 was up-regulated. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool size increased, which activated FXR and inhibited CYP7A1 despite continued activation of LXRalpha. Thus, in rabbits, when FXR and LXRalpha are activated simultaneously, the inhibitory effect of FXR overrides the stimulatory effect of LXRalpha to suppress CYP7A1 mRNA expression. |
| G to A substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI and high density lipoprotein cholesterol concentrations Jeenah, M., A. Kessling, et al. (1990), Mol Biol Med 7(3): 233-41. Abstract: We have determined the sequence of 250 bases 5' of the transcriptional start site of the apolipoprotein AI gene in a human individual with high serum concentrations of apo AI. One of the alleles contained a G to A substitution at position -75, between the CACAT sequence and the TAAATA box, creating a tandem repeat, CAGGGC-CA*GGGC. The substitution destroys an MspI cutting site, and the polymerase chain reaction and MspI digestion were used to identify the presence of the A or G base. The frequency of the A substitution in 96 healthy men from Bristol was 0.11 and this was increased to 0.25 in men with serum apo AI concentrations greater than 180 mg/dl. Men with the A allele had significantly higher serum concentrations of apo AI, high density lipoprotein (HDL) cholesterol and HDL2 than those with the G allele. In this sample, variation associated with the G to A substitution accounted for 6% and 4.6% of the total variance in apo AI and HDL cholesterol concentrations, respectively. Although there is as yet no functional proof, it is possible that the A substitution may be having a direct positive effect on the rate of apo AI gene transcription and thus be associated with increased apo AI and HDL cholesterol concentrations because of increased production of apo AI protein from the liver or intestine. |
| G-->A substitution at position -75 of the apolipoprotein A-I gene promoter. Evidence against a direct effect on HDL cholesterol levels Minnich, A., G. DeLangavant, et al. (1995), Arterioscler Thromb Vasc Biol 15(10): 1740-5. Abstract: The present study sought to resolve the contradictory evidence as to whether the G-->A substitution at position -75 of the apoA-I gene promoter raises HDL cholesterol (HDL-C) levels by examining the effect of this polymorphism in French Canadians, a relatively genetically homogeneous population. Among 308 women, carriers of the A allele displayed 12% and 10% higher mean plasma HDL-C and apoA-I concentrations, respectively, than did noncarriers. Among 345 men, no effect of the A allele was noted. The frequency distribution of HDL-C levels in women carrying the A but not the G allele appeared bimodal, with one peak corresponding to the mean of the noncarriers and a second to higher HDL-C. Thus it appears that only a subset of A alleles confers high HDL-C levels. This hypothesis was supported by data from four kindreds within which some but not all A alleles segregated with hyperalphalipoproteinemia. The data suggest that the A substitution in the apoA-I gene promoter does not directly confer high HDL-C levels but may be in linkage disequilibrium with other sequence polymorphism(s) at this locus in a subset of alleles that raise HDL-C levels. |
| Galactosylsucrose and xylosylfructoside alter digestive tract size and concentrations of cecal organic acids in rats fed diets containing cholesterol and cholic acid Hoshi, S., T. Sakata, et al. (1994), J Nutr 124(1): 52-60. Abstract: Influences of galactosylsucrose and xylosylfructoside on body mass gain, the digestive tract mass and concentrations of organic acids such as acetic, propionic, butyric, lactic and succinic acid in the cecum were compared among rats fed a cholesterol-enriched fiber-free diet cholesterol 6 + cholic acid 1.5 (g/kg) containing either galactosylsucrose, xylosylfructoside or sucrose (100 g/kg) or the above fiber-free diet without test sugar (control) for 21 d. Body mass gain was greater in rats fed sucrose, but not in rats fed galactosylsucrose or xylosylfructoside, than in control rats. The mass of the small intestine and colon plus rectum was larger in rats fed xylosylfructoside than in control rats. Cecal contents and cecal tissue mass were heavier, water content of cecal contents was higher, and pH and ammonia concentration of cecal contents were lower in rats fed diets containing xylosylfructoside than in control rats. Galactosylsucrose had similar effects, although not all differences were significant. The concentration of hydrogen ion in cecal contents positively correlated to total cecal concentration of measured organic acids and to amount of cecal contents. Total concentration of measured organic acids in cecal contents positively correlated to cecal tissue mass. The estimated contribution of galactosylsucrose, xylosylfructoside and sucrose for body mass deposition were 0.19, -0.29 and 0.51 (g body mass gained/g sugar), respectively. |