| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| A genomewide search using an original pairwise sampling approach for large genealogies identifies a new locus for total and low-density lipoprotein cholesterol in two genetically differentiated isolates of Sardinia Falchi, M., P. Forabosco, et al. (2004), Am J Hum Genet 75(6): 1015-31. Abstract: A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites. |
| A glucomannan and chitosan fiber supplement decreases plasma cholesterol and increases cholesterol excretion in overweight normocholesterolemic humans Gallaher, D. D., C. M. Gallaher, et al. (2002), J Am Coll Nutr 21(5): 428-33. Abstract: OBJECTIVE: Both chitosan and glucomannan have demonstrated hypocholesterolemic effects. A recent study in rats indicates that the combination of the two is also a potent hypocholesterolemic agent that increases fecal fat excretion. The objective of the present study was to determine the hypocholesterolemic effect of a supplement containing equal amounts of chitosan and glucomannan on blood lipid concentrations and fecal excretion of fat, neutral sterols and bile acids. METHODS: Twenty-one overweight normocholesterolemic subjects (11 males and 10 females) were fed 2.4 g/day of a supplement containing equal amounts of chitosan and glucomannan. Prior to taking the supplement (initial period) and after 28 days (final period), blood was drawn for measurement of serum lipids and a three-day fecal sample collected for determination of fat, neutral sterol and bile acid excretion. Subjects maintained their normal dietary and activity patterns during the study. RESULTS: Caloric intake and intake of fat and dietary fiber (excluding the supplement) did not differ between the initial and final periods. Serum total, HDL and LDL cholesterol concentrations were significantly lower (p < 0.05) in the final period compared to the initial period. Serum triacylglycerol concentration did not change between periods. There was a trend towards greater fecal excretion of neutral sterols and bile acids (p = 0.13 and 0.16, respectively) in the final period. However, fecal fat excretion did not differ between periods. CONCLUSIONS: Serum cholesterol reduction by a chitosan/glucomannan supplement is likely mediated by increased fecal steroid excretion and is not linked to fat excretion. |
| A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol Guerra, R., J. Wang, et al. (1997), Proc Natl Acad Sci U S A 94(9): 4532-7. Abstract: Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 1465 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction (approximately 25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 +/- 11 vs. 37 +/- 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 +/- 23 vs. 122 +/- 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 +/- 3 mg/dl) and apolipoprotein AI (153 +/- 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels. |
| A high cholesterol diet ameliorates renal tubular lesions in diabetic rats Reyes, A. A., J. Kissane, et al. (1990), Proc Soc Exp Biol Med 194(3): 177-85. Abstract: These studies examine the effect of cholesterol feeding in normal rats and in rats with streptozotocin-induced diabetes mellitus. Four groups were studied: normal rats fed either a standard rat chow or a standard rat chow supplemented with cholesterol and diabetic rats fed standard chow or standard chow plus cholesterol. Diabetic rats fed a standard diet excreted more creatinine and urea in the urine, had higher levels of blood urea nitrogen, and lower serum albumin levels than rats fed standard diet plus cholesterol. Blood glucose levels were similar in the two groups; however, diabetic rats given cholesterol had a greater body weight at the end of the study than diabetic rats eating standard chow. Urine volumes and sodium and potassium excretion in the urine were greater in diabetic rats fed a standard diet than in those fed a high cholesterol diet. Diabetic rats fed a standard diet had distinctive renal lesions characterized by swelling of tubular epithelial cells with clearing of cytoplasm. The nephron segments involved by this striking vacuolar change were the distal convoluted tubule and the thick limbs of Henle's loop. These lesions were identical to those described by Armanni-Ebstein in severely glycosuric patients. These lesions were not observed in any of the animals of the other three groups (including diabetic rats fed a high cholesterol diet). Glomeruli were normal in animals of all groups. Thus, cholesterol administration prevents the development of the Armanni-Ebstein lesions in diabetic rats despite persistent hyperglycemia. The mechanism by which cholesterol administration prevents the accumulation of glycogen in distal tubule cells has not been elucidated. It is suggested that glycogen accumulation in distal tubular segments may explain the greater urine volumes, natriuresis, kaliuresis, and proteinuria observed in diabetic animals fed a standard diet when compared with rats fed the same diet plus cholesterol. |
| A high cholesterol diet blocks the effect of calcium channel blockers on the uptake of sugars in rabbit intestine Hyson, D. H., A. B. Thomson, et al. (1997), Can J Physiol Pharmacol 75(1): 57-64. Abstract: Two classes of calcium channel blockers, nisoldipine (NIS) and verapamil (VER), alter the intestinal uptake of sugars, and varying the lipid composition of the diet also modifies intestinal transport function. This study was undertaken in adult male New Zealand rabbits to assess the effect of 3 weeks of dosing with NIS (1 mg.kg-1.day-1) or VER (4 mg.kg-1.day-1) on the in vitro jejunal uptake of D-galactose and L- or D-glucose. The value of the maximal transport rate of D-galactose (Vmax) increased with NIS and VER, compared with control vehicle. The value of the apparent Michaelis constant (K(m)) rose with NIS and fell with VER, and the value of the passive permeability coefficient (Pd) estimated from the uptake of L-glucose fell with NIS and rose with VER. These effects of NIS and VER on Vmax, K(m), and Pd were prevented by feeding a high cholesterol (2.8%) supplemented chow diet (HCD), as compared with chow alone. These effects were not due to any change in the animal's weight gain or intestinal mucosal surface area. The acute exposure of the jejunal tissue in vitro to varying concentrations of NIS but not VER reduced the uptake of D-glucose but had no effect on basal short circuit current (Isc) in either chow or HCD. Isc stimulated with glucose or theophylline was less in chow-fed rabbits compared with HCD-fed rabbits given NIS or VER. Thus, the active transport of sugars by the sodium-dependent transporter in the brush-border membrane, SGLT1, and the passive uptake by the paracellular route are variably influenced by these two classes of calcium channel blockers, and this effect is modified by the cholesterol content of the diet. |
| A high cholesterol, (n-3) polyunsaturated fatty acid diet induces hypercholesterolemia more than a high cholesterol (n-6) polyunsaturated fatty acid diet in hamsters Lu, S. C., M. H. Lin, et al. (1996), J Nutr 126(7): 1759-65. Abstract: This study was designed to study the effects of (n-3) polyunsaturated fatty acids (PUFA) on plasma and liver lipids, particularly lipoprotein cholesterol concentrations, in hamsters. Diets rich in (n-3) PUFA (21 g/100 g fatty acid) or (n-6) PUFA (37.4 g/ 100 g fatty acid) with or without 5 g/kg cholesterol (C) supplements were given for 4 wk to male hamsters weighing 70-90 g. The VLDL- and (IDL + LDL)-cholesterol concentrations were 114 and 128% higher in hamsters fed the (n-3) PUFA + C diet than in those fed the (n-6) PUFA + C diet. However, these differences were not observed when cholesterol was not supplemented. Hamsters fed the (n-3) PUFA diet had significantly lower plasma and hepatic triglyceride concentrations than those fed the (n-6) PUFA diet. Concentrations were comparable in hamsters fed (n-6) PUFA + C and (n-3) PUFA + C. Hepatic cholesteryl esters were significantly lower, while hepatic microsomal acyl-CoA:cholesterol acyltransferase activity and VLDL cholesteryl esters were significantly higher in hamsters fed the (n-3) PUFA + C diet than in those fed the (n-6) PUFA + C diet. Our results demonstrate that elevation of VLDL- and (IDL + LDL)-cholesterol in hamsters by (n-3) PUFA, compared with (n-6) PUFA, is dependent on dietary cholesterol supplementation and may be due to decreased catabolism of these lipoproteins. |
| A high low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio as a potential risk factor for corticosteroid-induced osteonecrosis in rabbits Miyanishi, K., T. Yamamoto, et al. (2001), Rheumatology (Oxford) 40(2): 196-201. Abstract: OBJECTIVE: This study was designed to determine the potential risk factors for corticosteroid-induced osteonecrosis (ON) based on lipid metabolism, using a rabbit ON model. METHODS: Blood samples were obtained from 38 rabbits, which then received a single intramuscular injection of 20 mg/kg methylprednisolone acetate. Four weeks after the injection, the femora and humeri were examined histopathologically for the presence of ON, and the sizes of the bone marrow fat cells were also measured. RESULTS: Rabbits with and without ON differed significantly in the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL/HDL cholesterol ratio), which is considered to be a serological marker of lipid transport (P=0.026). The marrow fat cells were significantly larger in the rabbits with ON than in those without ON (P<0.0001). CONCLUSION: A higher LDL/HDL cholesterol ratio was significantly associated with the development of ON, and such an elevated ratio may partly contribute to the increased size of marrow fat cells. |
| A high selectivity cascade filtration technique for LDL-cholesterol and Lp(a) removal Legallais, C., P. Moriniere, et al. (1995), Artif Organs 19(9): 887-95. Abstract: This work proposes an improvement of the cascade filtration technique in the treatment of familial hypercholesterolemia. A model of the whole process permitted the definition of the parameters that could influence the selectivity of the fractionation: the pore size, the sieving coefficients of both fractionation and plasmapheresis membrane, and the final retentate flow rate. In vivo studies have shown that the dead-end mode for the secondary filter was not always practical because of severe membrane plugging except when a pulsatile pump was included in the extracorporeal circuit. This pump generated hydrodynamic instabilities which decreased membrane fouling and retarded the build up of the polarization concentration layer. Optimization of these specific operating conditions permitted increase in the selectivity index from 1.15 to 2.24. The performances of cascade filtration were then comparable to those of adsorption on dextran sulfate columns. |
| A hydroxyethylated cholesterol-based cationic lipid for DNA delivery: effect of conditioning Percot, A., D. Briane, et al. (2004), Int J Pharm 278(1): 143-63. Abstract: We have synthesised a novel cholesterol-based cationic lipid to promote DNA transfer in cells. This lipid, dimethyl hydroxyethyl aminopropane carbamoyl cholesterol iodide (DMHAPC-Chol) contains a biodegradable carbamoyl linker and a hydroxyethyl group in the polar amino head moiety and is characterised by NMR. Liposomes prepared from this lipid and dioleoyl phosphatidyl ethanolamine (DOPE) in equimolar proportion showed a weak cytotoxicity as revealed by MTT assays and are efficient to deliver plasmids DNA evaluated by the expression of reporter genes in vitro and in vivo. In this paper, we present an original method to determine the lipid concentration based on the colorimetric detection of the colipid DOPE and the measure of the molar ratio DOPE/cationic lipid in the liposome by FTIR spectroscopy. The liposomes and lipid/DNA complexes structures were characterized by transmission electron microscopy (TEM) and by quasi-elastic light scattering (QLS). TEM indicated that the complexes correspond to aggregates containing globular substructures with liposomes size. The method of immuno-gold labelling was used to detect plasmid in the complex and reveals the presence of DNA inside the aggregates. Transfection results showed efficient DNA transfer depending on the charge ratio and liposomes conditioning. Gel retardation results indicated that at a molar charge ratio between X = 1.5 and X = 2.5 (depending on the liposome conditioning), all DNA was taken by liposomes. We showed that conditioning by freeze-drying (lyophilization) facilitates storage and improves transfection efficiency. When the liposomes were lyophilized prior to DNA addition or when the complexes were subjected to freeze-thawing cycles, the obtained complexes showed a transfection with levels enhanced up to four and five-fold respectively for the lyophilized liposomes and freeze-thawed complexes. NMR was used to characterize the modifications under freezing which showed an effect on 31P spectra. |
| A hydroxysteroid sulfotransferase, st2b2, is a skin cholesterol sulfotransferase in mice Shimada, M., Y. Kamiyama, et al. (2002), J Biochem (Tokyo) 131(2): 167-9. Abstract: The mRNA of a sulfotransferase (St2b2) mediating cholesterol sulfation was detected in mouse skin. Recombinant St2b2 also mediated the sulfation of pregnenolone, 3beta-hydroxy-5-cholen-24-oic acid, and dehydroepiandrosterone. St2b2 protein was detected in skin cytosols on Western blotting. The addition of 10 nM TPA to skin epidermal cells from newborn mice resulted in a twofold increase in cholesterol sulfation and concomitantly enhanced the St2b2 content after 40 h. Other candidate cholesterol sulfotransferases, St2a4 and St2a9, were not detected in skin by RT-PCR. These results indicate that St2b2 is a cholesterol sulfotransferase in mouse skin. |
| A keyhole middle fossa approach to large cholesterol granulomas of the petrous apex Cristante, L. and M. A. Puchner (2000), Surg Neurol 53(1): 64-70; discussion 70-1. Abstract: OBJECTIVE: In this article we review our surgical experience in a series of eight patients with large cholesterol granulomas of the petrous apex extending into the cerebellopontine angle. METHODS: All lesions, four primary and four recurrent, were studied with magnetic resonance imaging (MRI), and computed tomography (CT). The patients underwent pre- and postoperative audiographic testing. A keyhole middle fossa approach was used in all cases. RESULTS: There was no mortality. Surgery was complicated in one case by a subgaleal hematoma and in another by a transitory increase of a preexisting facial palsy. In five cases the granuloma was totally resected, whereas in the remaining three small remnants of the pseudocapsule were left in place. At follow-up (12-90 months), three patients were asymptomatic. In the remaining five patients, trigeminal neuralgias had subsided. Palsies of the VIth cranial nerve recovered more consistently than those of the VIIth. Hearing was unchanged postoperatively. So far, there has been no clinical or radiological evidence of a recurrence. CONCLUSION: Large cholesterol granulomas of the petrous apex can be effectively treated through a keyhole middle fossa approach. Despite its contained size the approach allows a rather large exposure of the granuloma. The resection of these lesions carries a low risk of compromising the facial or hearing function of the patient. Small remnants of the capsule, left in place to avoid potential complications, seem not to affect the long-term outcome of the patients, provided the cavity in the petrous bone is adequately ventilated. |
| A kinetic model to evaluate cholesterol efflux from THP-1 macrophages to apolipoprotein A-1 Gaus, K., J. J. Gooding, et al. (2001), Biochemistry 40(31): 9363-73. Abstract: The kinetics (0 to 3 h) of cholesterol efflux to delipidated apolipoprotein A-1 were investigated, and the experimental data were best fitted to a mathematical model that involves two independent pathways of cholesterol efflux. The first pathway with a rate constant of 4.6 h(-1) is fast but removes only 3-5% of total cholesterol. After preconditioning apoA-1, it was found that this pathway remains, and hence it is a property of the cholesterol-loaded cells rather than due to modification on the apolipoprotein. This fast initial efflux does not seem to contribute to cholesterol efflux at later stages (>1 h) where a second pathway predominates. However, the fast initial efflux pool can be restored if apoA-1 is withdrawn. The second slower pathway (k(membrane--media) = 0.79 h(-1)) is associated with cholesterol ester hydrolysis whose rate constant could be experimentally verified (k(cal) = 0.43, k(exp) = 0.38 +/- 0.05). The model suggests that two different plasma membrane domains are involved in the two pathways. Loading of the cells with an oxysterol, 7-ketocholesterol (7K), inhibits efflux from both pathways. The model predicts that 7K decreases the initial efflux by decreasing the available cholesterol (by possibly affecting lipid packing), while all rate constants in the second pathway are decreased. In conclusion, the kinetic model suggests that cholesterol efflux to apoA-1 is a two-step process. In the first step, some of the plasma membrane cholesterol contributes to a fast initial efflux (possibly from lipid rafts) and leads to a second pathway that mobilizes intracellular cholesterol mobilization. |
| A laboratory based intervention to improve appropriateness of lipid tests and audit cholesterol lowering in primary care Smellie, W. S., R. Lowrie, et al. (2001), Bmj 323(7323): 1224-7. Abstract: PROBLEM: A need exists to reduce inequalities in lipid testing, to provide relevant, individual, patient based interpretation for users, and to audit lipid lowering in primary care. DESIGN: Model to compare laboratory activity between different general practices; construction of computer based strategies to define the lipid tests to be done and to interpret results for primary and secondary coronary prevention patients; introduction of the strategies into routine use; monitoring of any change after the intervention; and investigation of the potential of the strategies to produce audit data for primary care groups. BACKGROUND AND SETTING: Hospital clinical laboratory serving 22 general practices covering 150 000 patients in Bishop Auckland area County Durham. Key measurements for improvement: Reduction in differences in testing for the different serum lipids in coronary prevention. Production of usable audit data for the primary care groups involved. Strategies for change: Four different categories of coronary prevention patient, with, for each category, the defined lipid tests to be done and advice to be given (based on the results), using the computer based strategies. EFFECTS OF CHANGE: Standardised test activity and the qualitative profile of the tests performed changed significantly. The strategies were readily adopted (median use 78%) within six months of introduction. LESSONS LEARNT: Computer based strategies can correct qualitative and quantitative differences in test requesting, provide interpretative guidance in accordance with national guidelines, and offer a cost effective model to monitor results of cholesterol lowering in general practice. |
| A Link between cholesterol levels and phenobarbital induction of cytochromes P450 Ourlin, J. C., C. Handschin, et al. (2002), Biochem Biophys Res Commun 291(2): 378-84. Abstract: Squalestatin1 (SQ1), a potent inhibitor of squalene synthase produced a dose-dependent induction of cytochromes P450 CYP2H1 and CYP3A37 mRNAs in chicken hepatoma cells. The effect of SQ1 was completely reversed by 25-hydroxycholesterol. Bile acids elicited an induction of CYP3A37 and CYP2H1 mRNA. Bile acids also reduced the phenobarbital induction of CYP2H1 but not of CYP3A37 mRNA. The effects of SQ1 and its reversal by 25-hydroxycholesterol and the effects of bile acids were reproduced in reporter gene assays with a phenobarbital-responsive enhancer unit of CYP2H1. These data suggest that an endogenous molecule related to cholesterol homeostasis regulates induction of drug-inducible CYPs. |
| A link between cholesterol, synapse plasticity, degeneration and neurological disorders: reinvention or integration? Koudinov, A. (2003), Bioessays 25(7): 736-7; author reply 737. |
| A linoleic acid enriched diet increases serum cholesterol esterification by lecithin:cholesterol acyltransferase in meal-fed rats Romijn, D., S. A. Wiseman, et al. (1998), Ann Nutr Metab 42(4): 244-50. Abstract: Dietary fats are known to influence the fatty acid profile of plasma lipids, including phospholipids which are substrates of lecithin:cholesterol acyltransferase (LCAT; EC 2.3.1.43), an important enzyme in lipoprotein metabolism. We tested whether the dietary fatty acid profile has an effect on LCAT activity in an animal model. Rats were conditioned to eat two meals per day, which were enriched in either palmitic, oleic or linoleic acids, for 10 weeks. Serum was isolated from blood samples taken prior to the meal. The LCAT activity was determined in two ways: (1) by measuring serum cholesterol esterification rates, which are an estimate of LCAT action on endogenous lipoproteins, and (2) by measuring serum LCAT activity levels with excess exogenous substrates, an estimate of LCAT mass. Animals receiving the linoleic acid diet had lower serum concentrations of unesterified cholesterol and triglycerides, if compared with animals fed oleic acid or palmitic acid diets (p < 0.05). Serum LCAT activity levels (measured with excess exogenous substrates) were not different, but both the absolute and fractional rates of cholesterol esterification were highest on the linoleic acid rich diet (p < 0.01), showing that LCAT action on endogenous lipoproteins is improved. No differences were found in serum apolipoprotein B and A-IV concentrations between the dietary groups. Apolipoprotein A-I levels were lowest in the palmitic acid group (oleic and linoleic > palmitic; p < 0.05), and apolipoprotein E levels were highest in the palmitic acid group (palmitic > oleic and linoleic; p < 0.05). It is concluded that a linoleic acid rich diet may cause increased metabolism of serum cholesterol by LCAT in rats. This effect is not due to elevated serum concentrations of LCAT or of its apolipoprotein activators, but most likely to changes in the chemical composition of endogenous lipoprotein substrates. It remains to be established whether the serum cholesterol esterification rates measured in vitro are related to in vivo rates of reverse cholesterol transport. |
| A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis Reymer, P. W., E. Gagne, et al. (1995), Nat Genet 10(1): 28-34. Abstract: A reduction of high density lipoprotein cholesterol (HDC) is recognized as an important risk factor for coronary artery disease (CAD). We now show in approximately 1 in 20 males with proven atherosclerosis that an Asn291Ser mutation in the human lipoprotein lipase (LPL) gene is associated with significantly reduced HDL levels (P = 0.001) and results in a significant decrease in LPL catalytic activity (P < 0.0009). The relative frequency of this mutation increases in those patients with lower HDL cholesterol levels. In vitro mutagenesis and expression studies confirm that this change is associated with a significant reduction in LPL activity. Our data support the relationship between LPL activity and HDL-C levels, and suggest that a specific LPL mutation may be a factor in the development of atherosclerosis. |
| A lipoprotein-cholesterol-albumin serum substitute stimulates Giardia lamblia encystation vesicle formation Reiner, D. S., M. L. Hetsko, et al. (1995), J Eukaryot Microbiol 42(5): 622-7. Abstract: We found previously that the A6 clone of Giardia lamblia strain WB that did not encyst in vitro was blocked at an early stage in differentiation, as it did not form encystation secretory vesicles (ESV) efficiently or express cyst antigens, in comparison with the related clone C6. We now report that A6 formed ESV normally in the suckling mouse model. Therefore, we asked whether our serum-containing encystation media might lack a stimulus or component or contain an inhibitor of ESV formation to which A6 was especially sensitive. We found that replacing bovine serum with a lipoprotein-cholesterol solution and bovine serum albumin (LPC) in pre-encystation and encystation media increased ESV formation by both A6 and C6. The % of A6 cells with ESV increased from 8% in BS medium to 48% in LPC medium, compared with 64% and 98% for C6. Similarly, the average number of ESV/positive cell increased from 1.5 in BS medium to 7.7 in LPC medium for A6, and from 13.3 to 19.7 for C6. Moreover, in LPC encystation media, A6 expressed the cyst wall epitope recognized by monoclonal GCSA-1. Although formation of water-resistant cysts by A6 was increased > 60 fold in LPC media, the numbers of cysts remained only approximately 3-15% that of C6. This suggests that LPC may primarily affect early events in encystation and that A6 may require additional factors later in encystation. |
| A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes Liang, Y., S. Lin, et al. (2004), J Neurochem 88(3): 623-34. Abstract: Apolipoprotein E (apoE) is an important protein involved in lipoprotein clearance and cholesterol redistribution. ApoE is abundantly expressed in astrocytes in the brain and is closely linked to the pathogenesis of Alzheimer's disease (AD). We report here that small molecule ligands that activate either liver X receptors (LXR) or retinoid X receptor (RXR) lead to a dramatic increase in apoE mRNA and protein expression as well as secretion of apoE in a human astrocytoma cell line (CCF-STTG1 cells). Examination of primary mouse astrocytes also revealed significant induction of apoE mRNA, and protein expression and secretion following incubation with LXR/RXR agonists. Moreover, treatment of mice with a specific synthetic LXR agonist T0901317 resulted in up-regulation of apoE mRNA and protein in both hippocampus and cerebral cortex, indicating that apoE expression in brain can be up-regulated by LXR agonists in vivo. Along with a dramatic induction of ABCA1 cholesterol transporter expression, these ligands effectively mediate cholesterol efflux in both CCF-STTG1 cells and mouse astrocytes in the presence or absence of apolipoprotein AI (apoAI). Our studies provide strong evidence that small molecule LXR/RXR agonists can effectively mediate apoE synthesis and secretion as well as cholesterol homeostasis in astrocytes. LXR/RXR agonists may have significant impact on the pathogenesis of multiple neurological diseases, including AD. |
| A locus influencing total serum cholesterol on chromosome 19p: results from an autosomal genomic scan of serum lipid concentrations in Pima Indians Imperatore, G., W. C. Knowler, et al. (2000), Arterioscler Thromb Vasc Biol 20(12): 2651-6. Abstract: A genome-wide linkage study was analyzed to identify loci that influence serum lipid concentrations in Pima Indians. Linkage analyses were conducted for total cholesterol measured in 998 siblings from 292 nuclear families, for total triglycerides in 547 siblings from 188 families, and for high density lipoprotein (HDL) cholesterol in 590 siblings from 201 families. Genotypes were generated for 516 autosomal microsatellite markers. Multipoint variance components methods were used to assess linkage. The strongest evidence for linkage with total cholesterol was on chromosome 19p (lod score 3.89), in the vicinity of the marker D19S1034, which is near the low density lipoprotein receptor gene. The strongest evidence for linkage with HDL cholesterol was on chromosome 3q (lod score 2.64) near D3S3053. For triglycerides, the strongest evidence for linkage was on chromosome 2p near D2S1788 (lod score 1.70) and on chromosome 3p near D3S2406 (lod score 1.77). This genomic scan provides evidence for a locus influencing total cholesterol concentration on chromosome 19p. It also suggests a locus influencing HDL cholesterol on chromosome 3q. |