| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Turpentine-induced inflammation reduces the hepatic expression of the multiple drug resistance gene, the plasma cholesterol concentration and the development of atherosclerosis in apolipoprotein E deficient mice Tous, M., V. Ribas, et al. (2005), Biochim Biophys Acta 1733(2-3): 192-8. Abstract: We aimed to investigate the effect of turpentine-induced inflammation in an atherosclerosis-prone murine model. We have induced a chronic aseptic inflammation in apolipoprotein E-deficient mice, with or without a dietary supplement of aspirin (n = 10, each), by the injection of a mixture (1:1) of turpentine and olive oil in the hind limb twice weekly for a period of 12 weeks. Control animals were injected with olive oil alone (n = 10). The control mice did show any alteration neither in plasma nor at the site of injection. Turpentine-treated mice showed a significant increase in plasma TNF-alpha and SAA concentrations which indicated a systemic inflammatory response that was not substantially affected by aspirin. Also, turpentine injections significantly reduced the plasma cholesterol concentration, probably decreasing intestinal cholesterol re-absorption, and attenuated the size of atherosclerotic lesion. Both effects were minimally influenced by aspirin. The burden of atherosclerosis correlated with plasma lipid levels but not with plasma inflammatory markers. Finally, there was a concomitant decrease in the expression of the hepatic mdr1b gene that correlated with the decrease in plasma cholesterol concentration. Therefore, we conclude that mdr1 is an additional factor to consider in the complexity of alterations in cholesterol metabolism that occur in this model. |
| Twenty four hour insulin infusion impairs the ability of plasma from healthy subjects and Type 2 diabetic patients to promote cellular cholesterol efflux Dullaart, R. P. and A. van Tol (2001), Atherosclerosis 157(1): 49-56. Abstract: Removal of cholesterol from peripheral cells by high density lipoproteins (HDL) is regarded as an important defence mechanism against atherosclerosis development. PLTP is involved in the generation of pre beta-HDL that can act as initial acceptors of cellular cholesterol. Exogenous hyperinsulinaemia may not only decrease HDL cholesterol, but also plasma phospholipid transfer protein (PLTP) activity. The effect of 24-h insulin infusion (30 mU/kg/h) on the ability of plasma to promote cholesterol efflux from Fu5AH cells was examined in eight healthy men and eight male Type 2 diabetic patients, matched for HDL cholesterol. Baseline HDL cholesterol and phospholipids, pre beta-HDL in incubated plasma, plasma apolipoprotein (apo) AI, PLTP activity and cholesterol efflux to plasma were not different between the groups. In both groups, HDL lipids, as well as plasma apo AI and PLTP activity decreased after 24 h of insulin (P<0.05 to P<0.01) compared to baseline and recovery, i.e. 1 week after insulin. Pre beta-HDL in incubated plasma did not significantly change. Cholesterol efflux to plasma from both groups decreased after insulin (P<0.05). Using plasma from healthy subjects, cholesterol efflux was correlated positively with HDL cholesterol, HDL phospholipids, pre beta-HDL in incubated plasma, plasma apo AI and PLTP activity (P<0.05 to P<0.001). Using plasma from diabetic patients, cholesterol efflux was not significantly correlated with any of these parameters. In conclusion, 24-h moderate hyperinsulinaemia impairs the ability of plasma to promote cholesterol efflux from Fu5AH cells. It is suggested that, apart from HDL, plasma PLTP activity is a determinant of cholesterol efflux via stimulation of pre beta-HDL formation. Cellular cholesterol efflux to plasma from selected Type 2 diabetic patients is maintained, but the interaction of Fu5AH cells with HDL may be altered. |
| Twenty-year dynamics of serum cholesterol levels in the middle-aged population of eastern Finland Jousilahti, P., E. Vartiainen, et al. (1996), Ann Intern Med 125(9): 713-22. Abstract: BACKGROUND: In cross-sectional analyses, serum cholesterol levels differ among different age groups. However, secular time trends in cholesterol levels can be seen across age groups in a population. A birth cohort analysis provides useful information on the combined effect of age and time on changes in serum cholesterol levels. OBJECTIVE: To analyze the 20-year dynamics of serum total cholesterol levels in relation to age, sex, birth cohort, time period, mortality rate, and changes in the intake of saturated fats. DESIGN: Cross-sectional measurements of serum total cholesterol levels in five independent population surveys done in 1972, 1977, 1982, 1987, and 1992. SETTING: Kuopio and North Karelia provinces in eastern Finland. PATIENTS: Random sample of 16,711 men and 17,542 women 25 to 64 years of age. Persons in the oldest birth cohort were born in 1913; persons in the youngest birth cohort were born in 1967. MEASUREMENTS: Total serum cholesterol levels and daily intake of dietary fat. RESULTS: Between 1972 and 1992, mean cholesterol levels decreased with time in each age group and for both sexes. According to the cross-sectional data, cholesterol levels increased with age and increased more steeply in women than in men. Contrary to these data, cholesterol levels in birth cohorts did not increase with age. Cholesterol levels did not change at all within birth cohorts of women and started to decrease after 45 years of age in birth cohorts of men. Cholesterol levels in the youngest birth cohorts (persons 25 to 29 years of age) entering the study each study year were markedly lower than levels in the same age group in the previous survey of risk factors. Daily intake of saturated fat decreased markedly between 1972 and 1992. Most of this decrease could be explained by change in intake of liquid dairy products and spreadable fats. In both sexes, changes in saturated fat intake were correlated with the time period, whereas the association with age was weak. CONCLUSIONS: In this Finnish population, total serum cholesterol levels are more closely associated with birth cohort than with age. Changes in dietary intake of saturated fat over time may account for changes in cholesterol levels. This finding suggests that community-based strategies for preventing cardiovascular disease can affect most of the population. |
| Two angiotensin AT1 receptor antagonists, irbesartan and losartan, effects in cholesterol-fed rabbits Sanz, M., P. Ganado, et al. (2002), Eur J Pharmacol 442(1-2): 99-106. Abstract: This study was performed to examine the long-term effects of irbesartan and losartan, two angiotensin (AT(1)) receptor antagonists, on lipoproteins and vascular responsiveness in vessels isolated from hypercholesterolemic rabbits. Four groups of rabbits (n=40) were used: Group 0 (control group), Group 1 hypercholesterolemic group, 0.5% (wt./wt.) cholesterol-enriched diet, Group 2 (hypercholesterolemic+irbesartan 10 mg/kg/day) and Group 3 (hypercholesterolemic+losartan 10 mg/kg/day). After 17 weeks of treatment, total cholesterol and low-density lipoproteins levels in irbesartan- and losartan-treated groups were significantly lower than those of Group 1 (alpha=0.05). Furthermore, levels of high-density lipoproteins were higher in the treated groups than in the hypercholesterolemic (alpha=0.05) when we consider the same level of total cholesterol in the hypercholesterolemic and the treated groups. Despite the effect of the drugs on the abovementioned parameters, treatment with irbesartan or losartan did not improve endothelium-dependent and independent relaxation in aortic and mesenteric rings. Treatment with irbesartan and losartan decreased noradrenaline-induced contraction in aortic rings with respect to that in the hypercholesterolemic group (alpha=0.05). In addition, irbesartan treatment improved the increase in serotonin-induced contraction in proximal coronary arteries with respect to that in the hypercholesterolemic group (alpha=0.05). These results indicate that irbesartan and losartan restore noradrenaline-induced contraction in hypercholesterolemic rabbit-isolated arteries and improve lipoprotein profile in cholesterol-fed rabbits. |
| Two cases of cholesterol granuloma of the breast Ishizaki, M., S. Ohsumi, et al. (2001), Breast Cancer 8(2): 158-61. Abstract: We report two cases of cholesterol granuloma of the breast clinically diagnosed as malignant and describe the features. The first patient was a 74-year-old woman who complained of a lump in the left breast. The mammography and ultrasonography suggested a malignant mass. Fine needle aspiration showed multinucleated giant cells. We suspected breast cancer, but cholesterol granuloma was diagnosed on excisional biopsy. The second case was a 51-year-old woman who was found to have a breast tumor on a screening mammography. The mammography and ultrasonography suggested carcinoma, but excisional biopsy revealed cholesterol granuloma. Reports of cholesterol granuloma of the breast are very rare. Cholesterol granuloma should be considered in the differential diagnosis of breast carcinoma. |
| Two families of Lowe oculocerebrorenal syndrome with elevated serum HDL cholesterol levels and CETP gene mutation Asami, T., K. Inano, et al. (1997), Acta Paediatr 86(1): 41-5. Abstract: The ocuolocerebrorenal syndrome of Lowe (OCRL) is an X-linked recessive disorder which is characterized by renal tubular dysfunction, congenital cataracts, and cognitive impairment. In a review article by Charnas et al. (N Engl J Med 1991; 324: 1318-25), hypercholesterolemia, due to elevated high-density lipoprotein cholesterol (HDL-C) levels, was described as being highly prevalent in OCRL patients. This report prompted us to examine three OCRL children in two unrelated families and we confirmed the high prevalence of high serum HDL-C levels in the patients (3/3). In addition, we found that their normal family members also had high serum HDL-C levels (5/7). Analysis of cholesteryl ester transfer protein (CETP) genes, which are now recognized as one of factors increasing serum HDLC levels, revealed the D442G mutation in exon 15 in 5 of 10 family members (1/3 of OCRL patients and 4/7 healthy family members), and no mutation of intron 14 G(+1)-to-A. The detected D442G mutation may be one of the causes in our two OCRL families; however, further studies, based on larger numbers of subjects, are needed to confirm these findings. |
| Two fatty acids can replace one phospholipid in condensed complexes with cholesterol Okonogi, T. M., A. Radhakrishnan, et al. (2002), Biochim Biophys Acta 1564(1): 1-4. Abstract: We report that the monolayer phase diagram for binary mixtures of dimyristoylphosphatidylethanolamine (DMPE) and dihydrocholesterol (DChol) is largely unchanged when each phospholipid molecule is replaced by two myristic acid (MA) molecules or various mixtures of the lysophospholipid and myristic acid. The corresponding phase diagrams all show the formation of "condensed complexes" of DChol and lipid. The condensed complex stoichiometry is thus largely determined by the C14 fatty acid acyl chains, in this case about 4-4.6 per DChol molecule. |
| Two major loci control variation in beta-lipoprotein cholesterol and response to dietary fat and cholesterol in baboons Rainwater, D. L., C. M. Kammerer, et al. (1998), Arterioscler Thromb Vasc Biol 18(7): 1061-8. Abstract: We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in beta-lipoproteins (low density lipoprotein cholesterol LDLC) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels (LDLC(Base)), we analyzed two variables for diet response: LDLC(RF), which represents the LDLC response to increasing dietary fat (ie, high-fat diet minus baseline), and LDLC(RC), which represents the LDLC response to increasing dietary cholesterol level (ie, high-cholesterol, high-fat diet minus high-fat diet). Heritabilities (h2) of the 3 traits were 0.59 for LDLC(Base), 0.14 for LDLC(RF), and 0.59 for LDLC(RC). In addition, LDLC(Base) and LDLC(RC) had a significant genetic correlation (ie, rhoG=0.54), suggesting that 1 or more genes exert pleiotropic effects on the 2 traits. Segregation analyses detected a single major locus that accounted for nearly all genetic variation in LDLC(RC) and some genetic variation in LDLC(Base) and LDLC(RF) and confirmed the presence of a different major locus that influences LDLC(Base) alone. Preliminary linkage analyses indicated that neither locus was linked to the LDL receptor gene, a likely candidate locus for LDLC. Detection of these major loci with large effects on the LDLC response to dietary cholesterol in a nonhuman primate offers hope of detecting and ultimately identifying similar loci that determine LDLC variation in human populations. |
| Two medium-chain acyl-coenzyme A synthetase genes, SAH and MACS1, are associated with plasma high-density lipoprotein cholesterol levels, but they are not associated with essential hypertension Haketa, A., M. Soma, et al. (2004), J Hypertens 22(10): 1903-7. Abstract: BACKGROUND AND OBJECTIVES: SAH has been proposed as a candidate gene for essential hypertension (EH) because elevated expression of SAH was observed in the kidneys of spontaneously hypertensive rats. Recently, a homology search of SAH in the human genome revealed the presence of the SAH gene family, which includes SAH, MACS1, MACS2, and MACS3. SAH and MACS1 are located within a 150-kb region on human chromosome 16p13.11. SAH and MACS1 are thought to function as acyl-coenzyme A synthetases, which are involved in fatty acid metabolism. In the present study, we analyzed six single nucleotide polymorphisms (SNPs) in the SAH and MACS1 genes in a Japanese population, and examined whether these SNPs contribute to EH and multiple risk factors. METHODS AND RESULTS: We performed association studies of six SNPs in 287 EH patients and 259 normotensive subjects. Multiple logistic linear regression analysis revealed that the allele frequencies of these six SNPs in SAH and MACS1 genes were not significantly different between EH patients and normotensives. SNP in exon 8 of the A/G polymorphism of the MACS1 gene and the G/T SNP in intron 3 of the SAH gene were associated with plasma levels of plasma high-density lipoprotein cholesterol. CONCLUSIONS: SNPs in the MACS1 and SAH genes contribute to plasma levels of high-density lipoprotein cholesterol. |
| Two moles of O2 consumption and one mole of H2O2 formation during cholesterol peroxidation with cholesterol oxidase from Pseudomonas sp. strain ST-200 Doukyu, N. and R. Aono (1999), Biochem J 341 (Pt 3): 621-7. Abstract: Cholesterol oxidase from Pseudomonas sp. strain ST-200 oxidized cholesterol and cholestanol to 6beta-hydroperoxycholest-4-en-3-one and 5alpha-cholestan-3-one respectively. The former was converted spontaneously to several oxysteroids such as 6-hydroxycholest-4-en-3-one and cholest-4-ene-3,6-dione, with the consumption of 2 mol of O(2) and the formation of 1 mol of H(2)O(2) for each mole of cholesterol oxidized. An oxidized form of the cholesterol oxidase dehydrogenates cholesterol, probably to the 5-en-3-one derivative. A reduced form of the enzyme, yielded from the cholesterol dehydrogenation reaction, dioxygenated cholest-5-en-3-one to 6beta-hydroperoxycholest-4-en-3-one. |
| Two patterns of lipid deposition in the cholesterol-fed rabbit Barnes, S. E. and P. D. Weinberg (1999), Arterioscler Thromb Vasc Biol 19(10): 2376-86. Abstract: A central feature of arterial lipid deposition is its nonuniform and variable distribution. In immature human and rabbit aortas, spontaneous lesions occur most frequently downstream of branch points, but they tend to occur upstream of the same branches at later ages. In cholesterol-fed rabbits, the juvenile pattern has been seen regardless of age. These distributions may be determined by transport properties of the arterial wall, because uptake of plasma macromolecules is elevated downstream of aortic branches in immature rabbits and upstream in mature ones, except during cholesterol feeding, when the juvenile pattern is seen in adult vessels. The effect of cholesterol could reflect its inhibitory influence on the nitric oxide (NO) pathway because the adult transport pattern is NO dependent. Using protocols expected to preserve NO function and the mature pattern of transport during hypercholesterolemia, we made 2 attempts to induce upstream disease in rabbits. In trial I, plasma concentrations of cholesterol were kept within the normal human range for 15 weeks by using dietary levels of 0.05% to 0.2%. Although disease patterns reverse with age in human vessels exposed to these concentrations, lesions in both immature and mature rabbits occurred downstream of intercostal branch ostia. Trial II used older rabbits, a different base diet containing more vitamin E (96 mg/kg rather than 57 mg/kg), and higher levels of cholesterol (1%, administered for 8 weeks). For some animals, extra vitamin E (2000 mg/kg) was added to the diet. The mature pattern of lipid deposition was apparent around intercostal branches in the first group and was accentuated by the additional vitamin E, a change that was associated with a significant increase in the plasma concentration of NO metabolites. Spontaneous lesions, assessed on the base diet, were too rare to have influenced these distributions. This is the first report of upstream disease in the cholesterol-fed rabbit. The results support but do not prove the view that NO and transport are important in atherogenesis. |
| Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol Bist, A., P. E. Fielding, et al. (1997), Proc Natl Acad Sci U S A 94(20): 10693-8. Abstract: Caveolae form the terminus for a major pathway of intracellular free cholesterol (FC) transport. Caveolin mRNA levels in confluent human skin fibroblasts were up-regulated following increased uptake of low density lipoprotein (LDL) FC. The increase induced by FC was not associated with detectable change in mRNA stability, indicating that caveolin mRNA levels were mediated at the level of gene transcription. A total of 924 bp of 5' flanking region of the caveolin gene were cloned and sequenced. The promoter sequence included three G+C-rich potential sterol regulatory elements (SREs), a CAAT sequence and a Sp1 consensus sequence. Deletional mutagenesis of individual SRE-like sequences indicated that of these two (at -646 and -395 bp) were essential for the increased transcription rates mediated by LDL-FC, whereas the third was inconsequential. Gel shift analysis of protein binding from nuclear extracts to these caveolin promoter DNA sequences, together with DNase I footprinting, confirmed nucleoprotein binding to the SRE-like elements as part of the transcriptional response to LDL-FC. A supershift obtained with antibody to SRE-binding protein 1 (SPEBP-1) indicated that this protein binds at -395 bp. There was no reaction at -395 bp with anti-Sp1 antibody nor with either antibody at -646 bp. The cysteine protease inhibitor N-acetyl-leu-leu-norleucinal (ALLN), which inhibits SREBP catabolism, superinhibited caveolin mRNA levels regardless of LDL-FC. This finding suggests that SREBP inhibits caveolin gene transcription in contrast to its stimulating effect on other promoters. The findings of this study are consistent with the postulated role for caveolin as a regulator of cellular FC homeostasis in quiescent peripheral cells, and the coordinate regulation by SREBP of FC influx and efflux. |
| Two subpopulations of intermediate density lipoprotein and their relationship to plasma triglyceride and cholesterol levels Meyer, B. J., M. J. Caslake, et al. (2000), Atherosclerosis 153(2): 355-62. Abstract: We observed the appearance of two intermediate density lipoprotein (IDL) subfractions on gradient gel electrophoresis of lipoproteins in the density range 1.006-1.030 g/ml and estimated their approximate concentrations in plasma in subjects with a wide range of lipid levels, from 0.55 to 28.0 mmol/l plasma triglyceride and 3.75-10.0 mmol/l cholesterol. The larger species, IDL-I (31.7 +/- 0.7 nm, mean +/- SD), showed little variation in size in normal and moderate hyperlipidaemic individuals. The estimated concentration of IDL-I was positively related to plasma triglyceride (r = 0.63, P = 0.0004) and low density lipoprotein (LDL) cholesterol (r = 0.68, P = 0.0003). These findings are consistent with the view that IDL-I is a metabolic intermediate between very low density lipoprotein (VLDL) and LDL. The smaller subfraction, IDL-II (25.7 +/- 2.4 nm) was virtually the only true species observed in subjects with plasma triglyceride < 1.0 mmol/l and its estimated concentration fell as plasma triglyceride increased (r = -0.58, P = 0.0002). IDL-II particle size changed in concert with LDL particle size (r = 0.61, P < 0.0001), suggesting that they were influenced by common metabolic factors. These observations provide further support for the hypothesis outlined by Musliner et al. 1 that IDL-I was part of the delipidation chain from VLDL to LDL, whereas IDL-II arose from a separate source, possibly directly released from the liver. Hence the two subpopulations of IDL differ in their relationship to plasma triglyceride and cholesterol levels. |
| Two-compartment model of cholesterol kinetics for establishment of treatment strategy of LDL apheresis in nephrotic hypercholesterolemia Yashiro, M., E. Muso, et al. (1994), Blood Purif 12(6): 317-26. Abstract: Cholesterol kinetics in the time course after LDL apheresis using a dextran sulfate cellulose column was analyzed by adapting a two-compartment cholesterol kinetic model. Fifteen sets of serial serum cholesterol concentrations after LDL apheresis from 4 patients with drug-resistant nephrotic hypercholesterolemia due to focal glomerulosclerosis (FGS) were analyzed and cholesterol kinetic parameters were estimated with the nonlinear least-squares method. The fractional cholesterol catabolic rates (Kc; 0.171 +/- 0.073/day, mean +/- SD) were markedly decreased as reported in familial hypercholesterolemia (homo: 0.101/day, hetero: 0.280/day). Cholesterol generation rates (G; 68.0 +/- 28.7 mg/dl/day, mean +/- SD) considerably overlapped the normal range (39.2-77.5 mg/dl/day). This result was compatible with an earlier report that Kc was reduced earlier than G in nephrotic hypercholesterolemia. The time average serum cholesterol concentrations (TAC) in the rebound phase after LDL apheresis can be simulated using these kinetic parameters by the Runge-Kutta-Gill method. According to our previous report, TAC must be reduced to under a near-normal level in order to obtain a beneficial effect on nephrotic syndrome due to FGS. In 10 sets out of the 15, once-weekly treatment of LDL apheresis was sufficient to achieve this aim, but in the remaining 5 cases, more frequent LDL apheresis up to twice a week was necessary in the early phase of treatment. In conclusion, the two-compartment cholesterol kinetic model is useful in clarifying the abnormal cholesterol kinetics in nephrotic syndrome and may be helpful in establishing a more rational strategy of LDL apheresis for nephrotic hypercholesterolemia. |
| Type C Niemann-Pick disease. Detection and quantification of cholesterol-accumulating cells in bone marrow Tohyama, J., M. Kato, et al. (1993), Brain Dev 15(4): 316-7. |
| Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver Goldin, E., C. F. Roff, et al. (1992), Biochim Biophys Acta 1127(3): 303-11. Abstract: We have determined the levels of free sphingoid bases in livers of normal and cholesterol lipidotic Niemann-Pick type C mice. Hepatic sphingosine and sphinganine levels in affected mice (593 pmol/mg protein) were elevated more than 20-fold when compared to levels in age-matched normal mice (26 pmol/mg protein). Upon fractionation of mutant liver homogenates by differential centrifugation, most of the sphingoid bases sedimented with beta-hexosaminidase in the 9000 x g pellet. Co-sedimentation of sphingoid bases with a lighter beta-hexosaminidase peak in Percoll gradients suggests that these bases accumulate in lipid laden lysosomes. A cytosolic sphinganine kinase is the first enzyme in the degradative pathway of sphingoid base metabolism. Activity of this enzyme was partially deficient in crude mutant liver cytosolic extracts due to the presence of an inhibitory substance. Following molecular sieving of mutant cytosolic extracts on Sepharose 4B, sphinganine kinase, with normal levels of activity, was resolved from a complex higher-molecular-weight inhibitor fraction. The Km values for either sphinganine or ATP-Mg substrates with partially purified sphinganine kinase from normal and mutant mouse liver extracts, were similar. These findings indicate that accumulation of free sphingoid bases is not due to a direct inherent deficiency in the catalytic activity of sphinganine kinase. The possible cause and effect relationship between the accumulation of these endogenous hydrophobic amines and the lesion in intracellular cholesterol trafficking in Niemann-Pick type C disease is discussed. |
| Type C Niemann-Pick disease: cellular uncoupling of cholesterol homeostasis is linked to the severity of disruption in the intracellular transport of exogenously derived cholesterol Argoff, C. E., M. E. Comly, et al. (1991), Biochim Biophys Acta 1096(4): 319-27. Abstract: A uniquely attenuated disruption of cholesterol homeostasis has been characterized in certain Niemann-Pick, type C (NP-C) fibroblasts. Uptake of LDL-cholesterol by cultured fibroblasts derived from two clinically affected brothers with this variant biochemical phenotype led to less intracellular accumulation of unesterified cholesterol than found in other typical cell lines. This limited cholesterol lipidosis in the variant NP-C cells reflected cholesterol processing errors that differed from the cellular lesions in classical NP-C cells in the following ways: (1) a more limited intracellular distribution of the excessive unesterified cholesterol; (2) shorter and more transient delays in the induction of cholesterol-mediated homeostatic responses; and (3) more efficient intracellular transport of exogenously derived cholesterol to the plasma membrane and the endoplasmic reticulum. Activation of acyl-CoA cholesterol acyltransferase (ACAT) was greater than 100-fold in both control and NP-C fibroblasts when cell cultures were preconditioned with 25-hydroxycholesterol, but the subsequent esterification of exogenous non-lipoprotein 3Hcholesterol remained deficient in all NP-C cells. In the variant NP-C cells conditioned with the oxysterol, this esterification of exogenous 3Hcholesterol was less affected than in classical NP-C cultures. The NP-C mutation affects a broad spectrum of metabolic responses related to the processing of exogenously derived cholesterol. Among this pleiotropic array of deficient responses, retarded intracellular cholesterol transport appears most closely linked to the primary mutation. This conclusion is supported by two current observations: (1) the degree to which sterol transport is affected in mutant cells in turn reflects the extent to which cholesterol-homeostatic responses are compromised; and (2) sterol transport remains deficient despite concurrent normal activation of other cellular responses, such as cholesterol esterification. |
| Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing Vanier, M. T., C. Rodriguez-Lafrasse, et al. (1991), Biochim Biophys Acta 1096(4): 328-37. Abstract: To investigate biochemical heterogeneity within Niemann-Pick type C disease (NPC), the two most characteristic abnormalities, namely (1) kinetics of LDL-stimulated cholesteryl ester formation and (2) intravesicular accumulation of LDL-derived unesterified cholesterol, evaluated by histochemical filipin staining, were studied in cultured skin fibroblasts from a population of 125 NPC patients. Profound alterations (esterification rates less than 10% of normal, very numerous and intensely fluorescent cholesterol-filipin granules) were demonstrated in 86% of the cases, depicting the 'classical' NPC phenotype. The remaining cell lines showed a graded less severe impairment and more transient delay in the induction of LDL-mediated cholesteryl esterification, along with an attenuated accumulation of unesterified cholesterol. In particular, cells from a small group (7%) of patients, which have been individualized as representative of a 'variant' phenotype, showed only slight alterations of esterification, restricted to the early phase of LDL uptake and undistinguishable from those in heterozygotes. In these cells, an abnormal cytochemical distribution of LDL-derived cholesterol, although moderate, was still evident provided rigorous experimental conditions were followed. A third, less clearly individualized group (7%), differing from the classical phenotype mostly by higher rates of cholesteryl ester formation, has been designated as an 'intermediary' phenotype to reflect a more difficult diagnosis of such patients. These findings have an important bearing with regard to diagnosis and genetic counselling, although the significance of such a phenotypic variation in terms of genetic heterogeneity has still to be demonstrated. A given biochemical phenotype was however a constant observation within a family (14 pairs of siblings tested so far). The unique feature of LDL-cholesterol processing alterations in NPC has been further established from comparative studies in Wolman disease and I-cell disease, showing normal or different intracellular distribution of unesterified LDL-derived cholesterol in the latter disorders. Correlation between biochemical and clinical NPC phenotypes was only partial, but a correlation between the severity of alterations in cholesterol processing and sphingomyelin catabolism could be established. |
| Type C Niemann-Pick disease: supranuclear ophthalmoplegia associated with deficient biosynthesis of cholesterol esters Turpin, J. C., J. Y. Goas, et al. (1991), Rev Neurol (Paris) 147(1): 28-34. Abstract: We report a familial case of Niemann-Pick disease type C which lasted until adulthood, and which had the characteristic deficiency in cholesterol esterification from exogenous cholesterol. A review of the literature was performed concerning cases which were seen in adults and were characterized biochemically. This study showed the frequency of supranuclear ophthalmoplegia affecting essentially vertical movements and convergence and of lipid-laden cells in bone marrow which are often sea-blue histiocytes. |
| Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport Roff, C. F., E. Goldin, et al. (1991), Dev Neurosci 13(4-5): 315-9. Abstract: Niemann-Pick Type C (NPC) disease is a cholesterol lipidosis resulting from defective postlysosomal cholesterol transport. In normal cells this segment of cholesterol trafficking is inhibited by treatment with either U18666A or imipramine. Other compounds are also capable of blocking postlysosomal cholesterol transport: stearylamine, RV-538, and sphinganine inhibit low-density lipoprotein-induced esterification of cholesterol and cause unesterified cholesterol to accumulate in perinuclear vesicles. These vesicles can be stained with filipin to give a staining pattern indistinguishable from that seen in NPC fibroblasts. Because all of these compounds are hydrophobic amines, we conclude that most, if not all, hydrophobic amines block the postlysosomal transport of cholesterol. These results also raise the possibility that an endogenous amine, e.g., sphinganine, may inhibit cholesterol transport in NPC. |