| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Niacin and cholesterol: role in cardiovascular disease (review) Ganji, S. H., V. S. Kamanna, et al. (2003), J Nutr Biochem 14(6): 298-305. Abstract: Niacin has been widely used as a pharmacologic agent to regulate abnormalities in plasma lipid and lipoprotein metabolism and in the treatment of atherosclerotic cardiovascular disease. Although the use of niacin in the treatment of dyslipidemia has been reported as early as 1955, only recent studies have yielded an understanding about the cellular and molecular mechanism of action of niacin on lipid and lipoprotein metabolism. In brief, the beneficial effect of niacin to reduce triglycerides and apolipoprotein-B containing lipoproteins (e.g., VLDL and LDL) are mainly through: a) decreasing fatty acid mobilization from adipose tissue triglyceride stores, and b) inhibiting hepatocyte diacylglycerol acyltransferase and triglyceride synthesis leading to increased intracellular apo B degradation and subsequent decreased secretion of VLDL and LDL particles. The mechanism of action of niacin to raise HDL is by decreasing the fractional catabolic rate of HDL-apo AI without affecting the synthetic rates. Additionally, niacin selectively increases the plasma levels of Lp-AI (HDL subfraction without apo AII), a cardioprotective subfraction of HDL in patients with low HDL. Using human hepatocytes (Hep G2 cells) as an in vitro model system, recent studies indicate that niacin selectively inhibits the uptake/removal of HDL-apo AI (but not HDL-cholesterol ester) by hepatocytes, thereby increasing the capacity of retained HDL-apo AI to augment cholesterol efflux through reverse cholesterol transport pathway. The studies discussed in this review provide evidence to extend the role of niacin as a lipid-lowering drug beyond its role as a vitamin. |
| Niacin decreases removal of high-density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implication for reverse cholesterol transport Jin, F. Y., V. S. Kamanna, et al. (1997), Arterioscler Thromb Vasc Biol 17(10): 2020-8. Abstract: Niacin (nicotinic acid) is the most potent clinically used agent for increasing plasma HDL and apolipoprotein (apo) A-I. The mechanism by which niacin increases apoA-I is not clearly understood. We have examined the effect of niacin on the hepatic production and removal of apoA-I using Hep G2 cells as an in vitro model. Incubation of Hep G2 cells with niacin resulted in increased accumulation of apoA-I in the medium in a dose-dependent manner. Incorporation of 3Hleucine and 35Smethionine into apoA-I and apoA-I mRNA expression was unchanged by niacin, suggesting that it did not affect apoA-I de novo synthesis. Uptake of radiolabeled HDL protein and HDL apoA-I by Hep G2 cells was significantly reduced to as much as 82.9 +/- 2.2% (P =.04) and 84.2 +/- 2.8% (P =.02), respectively, of the baseline with increasing concentrations of niacin (0 to 3.0 mmol/L). Specific 125I-HDL protein uptake measured with a 50-fold excess of unlabeled HDL was reduced to as much as 78.3 +/- 4.8% (P =.005) in niacin-treated cells. The uptake of labeled cholesterol esters in HDL was unaffected by niacin. Niacin also effected a similar decrease in HDL protein uptake, but not cholesterol esters, from apoA-I-containing HDL particles isolated by immunoaffinity. The conditioned medium obtained from Hep G2 cells incubated with niacin significantly (P =.002) increased cholesterol efflux from cultured human fibroblasts. These data indicate a novel mechanism whereby niacin selectively decreases hepatic removal of HDL apoA-I but not cholesterol esters, thereby increasing the capacity of retained apoA-I to augment reverse cholesterol transport. |
| Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol Sakai, T., V. S. Kamanna, et al. (2001), Arterioscler Thromb Vasc Biol 21(11): 1783-9. Abstract: Evidence indicates that the high density lipoprotein (HDL) subfraction containing apolipoprotein A-I without apolipoprotein AII (LP-AI) is more antiatherogenic than HDL particles containing apolipoprotein A-I and apolipoprotein A-II (LP-AI+AII). This study examined the effect of extended-release niacin (niacin-ER) and gemfibrozil on LP-AI and LP-AI+AII particles in patients with low levels of HDL cholesterol (HDL-C). Mechanisms by which these agents modulate HDL particles were investigated by in vitro studies using human hepatoblastoma (Hep G2) cells. A total of 139 patients with low HDL-C ( |
| Niemann-Pick C disease: cholesterol handling gone awry Morris, J. A. and E. D. Carstea (1998), Mol Med Today 4(12): 525-31. Abstract: Niemann-Pick C disease (NPC) is a debilitating, recessive disorder in humans that causes unrelenting neurological deterioration and is complicated by the presence of lipid-laden foamy cells in the major organs of the body. NPC fibroblasts cultured with an excess of low density lipoprotein (LDL) abnormally sequester cholesterol in their lysosomes. Biochemical analyses of NPC cells suggest an impairment in the intracellular transport of cholesterol to post-lysosomal destinations occurs in NPC. The recent identification of the NPC gene, NPC1, provides a definitive diagnosis of the disease and a means of studying this key component of intracellular cholesterol transport and homeostasis. |
| Niemann-Pick C disease: cystine and lipids accumulate in the murine model of this lysosomal cholesterol lipidosis Butler, J. D., M. T. Vanier, et al. (1993), Biochem Biophys Res Commun 196(1): 154-9. Abstract: Cystine levels in tissues of the murine BALB/C mouse model of type C Niemann-Pick disease were shown to be greatly elevated. Subcellular fractionation of liver homogenates by differential centrifugation suggested preferential accumulation in a fraction corresponding to lysosomes. Developmentally, a sharp increase in the accumulation of cystine in the mutant mouse liver occurs subsequent to a similar change in the accumulation of cholesterol, sphingomyelin and glucocerebroside. The lysosomal accumulation of cystine in this mutant mouse provides the experimental opportunity to study some aspects of the deficiency of lysosomal cystine transport noted in cystinosis. |
| Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis Carstea, E. D., J. A. Morris, et al. (1997), Science 277(5323): 228-31. Abstract: Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. |
| Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis Davis, H. R., Jr., L. J. Zhu, et al. (2004), J Biol Chem 279(32): 33586-92. Abstract: Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia. |
| Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption Altmann, S. W., H. R. Davis, Jr., et al. (2004), Science 303(5661): 1201-4. Abstract: Dietary cholesterol consumption and intestinal cholesterol absorption contribute to plasma cholesterol levels, a risk factor for coronary heart disease. The molecular mechanism of sterol uptake from the lumen of the small intestine is poorly defined. We show that Niemann-Pick C1 Like 1(NPC1L1) protein plays a critical role in the absorption of intestinal cholesterol. NPC1L1 expression is enriched in the small intestine and is in the brush border membrane of enterocytes. Although otherwise phenotypically normal, NPC1L1-deficient mice exhibit a substantial reduction in absorbed cholesterol, which is unaffected by dietary supplementation of bile acids. Ezetimibe, a drug that inhibits cholesterol absorption, had no effect in NPC1L1 knockout mice, suggesting that NPC1L1 resides in an ezetimibe-sensitive pathway responsible for intestinal cholesterol absorption. |
| Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae Garver, W. S., K. Krishnan, et al. (2002), J Lipid Res 43(4): 579-89. Abstract: The Niemann-Pick C1 (NPC1) protein regulates cholesterol transport from late endosomes-lysosomes to other intracellular compartments. In this article, cholesterol transport to caveolin-1 and caveolin-2 containing compartments, such as the trans-Golgi network (TGN) and plasma membrane caveolae, was examined in normal (NPC+/+), NPC heterozygous (NPC+/-), and NPC homozygous (NPC-/-) human fibroblasts. The expression and distribution of NPC1 in each cell type were similar, and characterized by a finely dispersed, granular staining pattern. The expression of caveolin-1 and caveolin-2 was increased in NPC+/- and NPC-/- fibroblasts, although the distribution in each cell type was similar and characterized by predominant staining of the TGN and plasma membrane. The TGN in NPC+/+ fibroblasts was relatively cholesterol-enriched, whereas the TGN in NPC+/- and NPC-/- fibroblasts was partially or completely cholesterol-deficient, respectively. Consistent with studies demonstrating the transport of cholesterol from the TGN to plasma membrane caveolae, the concentration of cholesterol in plasma membrane caveolae isolated from NPC+/- and NPC-/- fibroblasts was significantly decreased, even though the total concentration of plasma membrane cholesterol in each cell type was similar.These studies demonstrate that NPC1 regulates cholesterol transport to caveolin-1 and caveolin-2 containing compartments such as the TGN and plasma membrane caveolae. |
| Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization Watari, H., E. J. Blanchette-Mackie, et al. (1999), Proc Natl Acad Sci U S A 96(3): 805-10. Abstract: Niemann-Pick type C (NPC) disease is an inherited lipid storage disorder that affects the viscera and central nervous system. A characteristic feature of NPC cells is the lysosomal accumulation of low density lipoprotein-derived cholesterol. To elucidate important structural features of the recently identified NPC1 gene product defective in NPC disease, we examined the ability of wild-type NPC1 and NPC1 mutants to correct the excessive lysosomal storage of low density lipoprotein-derived cholesterol in a model cell line displaying the NPC cholesterol-trafficking defect (CT60 Chinese hamster ovary cells). CT60 cells transfected with human wild-type NPC1 contained immunoreactive proteins of 170 and 190 kDa localized to the lysosomal/endosomal compartment. Wild-type NPC1 protein corrected the NPC cholesterol-trafficking defect in the CT60 cells. Mutation of conserved cysteine residues in the NPC1 N terminus to serine residues resulted in proteins targeted to lysosomal membranes encircling cholesterol-laden cores, whereas deletion of the C-terminal 4-aa residues containing the LLNF lysosome-targeting motif resulted in the expression of protein localized to the endoplasmic reticulum. None of these mutant NPC1 proteins corrected the NPC cholesterol-trafficking defect in CT60 cells. We conclude that transport of the NPC1 protein to the cholesterol-laden lysosomal compartment is essential for expression of its biological activity and that domains in the N terminus of the NPC1 protein are critical for mobilization of cholesterol from lysosomes. |
| Niemann-Pick disease type C and cholesterol Ninomiya, H. and K. Ohno (1999), Tanpakushitsu Kakusan Koso 44(8 Suppl): 1213-8. |
| Niemann-Pick disease: coupling and uncoupling of inhibited sphingomyelinase activity and exogenous cholesterol esterification in fibroblasts by ionophore treatment Sakuragawa, N., T. Mito, et al. (1994), Biochim Biophys Acta 1213(2): 193-8. Abstract: In order to elucidate a biochemical relationship between sphingomyelin and cholesterol metabolisms, we examined the effects of several ionophores (monensin, nigericin, A23187, ionomycin, lasalocid) on sphingomyelinase activity and cholesterol esterification in cultured human fibroblasts. Phase-contrast microscopy showed the presence of foamy cells with monensin and nigericin treatments only. Electron microscopic examination revealed lamellated membranous bodies and cytoplasmic vacuoles in cells treated with monensin and nigericin. Monensin and nigericin treatments led to reduction of acid sphingomyelinase activity and disturbance of the esterification of lipoprotein-derived cholesterol in cultured fibroblasts, which is compatible with the biochemical changes of Niemann-Pick disease, type C. A23187, ionomycin, and lasalocid treatments showed only sphingomyelinase reduction in treated fibroblasts. Experimental models in this culture system could be produced in these ways, mimicking subtypes of Niemann-Pick disease, type A, B and type C. |
| Niemann-Pick type C disease and intracellular cholesterol trafficking Chang, T. Y., P. C. Reid, et al. (2005), J Biol Chem 280(22): 20917-20. |
| Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations Ribeiro, I., A. Marcao, et al. (2001), Hum Genet 109(1): 24-32. Abstract: Niemann-Pick type C disease (NPC) is a rare neurodegenerative disorder characterised by lysosomal/late endosomal accumulation of endocytosed unesterified cholesterol and delayed induction of cholesterol homeostatic reactions. The large majority of mutations in the NPC1 gene described thus far have been associated with severe cellular cholesterol trafficking impairment (classic biochemical phenotype, present in about 85% of NPC patients). In our population of 13 unrelated NP-C1 patients, among which 12 were of Portuguese extraction, we observed an unusually large proportion of families presenting mild alterations of intracellular cholesterol transport (variant biochemical phenotype), without strict correlation between the biochemical phenotype and the clinical expression of the disease. Mutational studies were carried out to compare molecular lesions associated with severe and mild cholesterol traffic impairment. Levels of NPC1 protein were studied by Western blot in cultured fibroblasts of four patients with homozygous mutant alleles. Ten novel mutations were identified (Q92R, C177Y, R518W, W942C, R978C, A1035V, 2129delA, 3662delT, IVS23+1 G>A and IVS16-82 G>A). The mutational profile appeared to be correlated with the biochemical phenotype. Splicing mutations, I1061T and A1035V, corresponded to "classic" alleles, while three missense mutations, C177Y, R978C and P1007A, could be defined as "variant" alleles. All "variant" mutations described so far appear to be clustered within the cysteine-rich luminal loop between TM 8 and 9, with the remarkable exception of C177Y. The latter mutant allele, at variance with P1007A, was correlated to a decreased level of NPC1 protein and a severe course of the disease, and disclosed a new location for "variant" mutations, the luminal loop located at the N-terminal end of the protein. |
| Niemann-Pick type C: a disorder of cellular cholesterol trafficking Ory, D. S. (2000), Biochim Biophys Acta 1529(1-3): 331-9. |
| Niemann-pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis Millard, E. E., K. Srivastava, et al. (2000), J Biol Chem 275(49): 38445-51. Abstract: The Niemann-Pick type C1 (NPC1) protein is a key participant in intracellular trafficking of low density lipoprotein cholesterol, but its role in regulation of sterol homeostasis is not well understood. To characterize further the function of NPC1, we generated stable Chinese hamster ovary (CHO) cell lines overexpressing the human NPC1 protein (CHO/NPC1). NPC1 overexpression increases the rate of trafficking of low density lipoprotein cholesterol to the endoplasmic reticulum and the rate of delivery of endosomal cholesterol to the plasma membrane (PM). CHO/NPC1 cells exhibit a 1.5-fold increase in total cellular cholesterol and up to a 2.9-fold increase in PM cholesterol. This increase in PM cholesterol is closely paralleled by a 3-fold increase in de novo cholesterol synthesis. Inhibition of cholesterol synthesis results in marked redistribution of PM cholesterol to intracellular sites, suggesting an unsuspected role for NPC1 in internalization of PM cholesterol. Despite elevated total cellular cholesterol, CHO/NPC1 cells exhibit increased cholesterol synthesis, which may be attributable to both resistance to oxysterol suppression of sterol-regulated gene expression and to reduced endoplasmic reticulum cholesterol levels under basal conditions. Taken together, these studies provide important new insights into the role of NPC1 in the determination of the levels and distribution of cellular cholesterol. |
| Niemann-Pick type II fibroblasts exhibit impaired cholesterol esterification in response to sphingomyelin hydrolysis Byers, D. M., M. W. Morgan, et al. (1992), Biochim Biophys Acta 1138(1): 20-6. Abstract: Fibroblasts from patients with Niemann-Pick Type II disease, including the panethnic type C (NPC) and Nova Scotia Acadian type D (NPD) forms, exhibit reduced or delayed stimulation of cholesterol esterification by low density lipoprotein (LDL). Based on recent evidence that cholesterol esterification can also be stimulated by cell surface sphingomyelin hydrolysis, we have compared the response of normal, NPC and NPD fibroblasts to treatment with exogenous sphingomyelinase (SMase). Staphylococcus aureus SMase (greater than 0.05 U/ml) hydrolyzed over 90% of endogenous sphingomyelin within 1 h and increased incorporation of 3Holeic acid into cholesterol-3Holeate after an initial lag in all three cell types. However, normal levels of cholesterol esterification were not observed for NP Type II fibroblasts: four NPD cell lines exhibited an average of 32% of normal response while cholesterol esterification was only 20% in two well-characterized NPC lines. A third NPC line exhibited normal response to SMase despite greater than 90% impairment of LDL-stimulated cholesterol esterification. Incubation of fibroblasts with LDL followed by SMase produced a synergistic response, particularly in NPC cells where there was little response to either treatment alone. Chloroquine abolished LDL-stimulated cholesterol esterification in normal fibroblasts but had no effect on the response to SMase, indicating that lysosomal enzymes may not be involved in SMase-mediated cholesterol esterification. These results suggest that intracellular processing of cholesterol derived from either LDL or release from the plasma membrane (by sphingomyelin hydrolysis) is affected in Niemann-Pick Type II cells and that these pathways can complement one another in the stimulation of cholesterol esterification. |
| Niemann-Pick type-C disease: deficient intracellular transport of exogenously derived cholesterol Roff, C. F., E. Goldin, et al. (1992), Am J Med Genet 42(4): 593-8. Abstract: NPC disease is an autosomal recessive neurovisceral storage disorder. A pleiotropic array of secondary enzymatic and storage abnormalities has in the past obscured a cohesive understanding of the underlying metabolic basis of this disorder. Recent findings, reviewed in this report, demonstrate that NPC disease is a cholesterol lipidosis resulting from defective intracellular cholesterol transport. The sequence of cellular events characteristic of NPC is 1) deficient intracellular transport of exogenously derived cholesterol resulting in retarded induction of cellular cholesterol homeostatic regulation; 2) accumulation of cholesterol in lysosomes; and 3) secondary cellular effects. Retarded esterification of exogenous cholesterol and accumulation of unesterified cholesterol in lysosomes is tightly coupled to the primary defect and serves as the basis for biochemical diagnosis of NPC. |
| Niemann-Pick-like liver disease and reduced cholesterol esterification in fibroblasts of two male infants Kristjansson, K., M. J. Finegold, et al. (1994), Eur J Pediatr 153(5): 347-51. Abstract: Niemann-Pick disease type C (NPC) presents in about half of the cases in the newborn period with jaundice, hepato-splenomegaly, and a clinical pattern similar to neonatal hepatitis. The definitive diagnosis can in most instances be made by the appropriate biochemical testing of lipoprotein stimulated cholesteryl ester synthesis and cholesterol accumulation in cultured patient fibroblasts. We report two infants who by liver biopsy had classical findings of NPC and a cholesteryl ester synthesis level about 50% of the normal lower limit. On the other hand neither of these patients' fibroblasts showed any evidence of low density lipoprotein-induced cholesterol accumulation, precluding the possibility of a definitive diagnosis. These cases demonstrate the importance of the appropriate biochemical testing before final counseling is carried out. The possibility of our patients representing allelic or non-allelic variants of NPC are discussed. |
| Nifedipine inhibits accumulation of LDL and cholesterol in the aorta of the normocholesterolemic rabbit Gorog, P. and G. V. Born (1993), Arterioscler Thromb 13(5): 637-9. Abstract: The effect of 5 days of oral nifedipine treatment (approximately 1 mg/kg per day in drinking water) on low density lipoprotein (LDL) and cholesterol accumulation in rabbit arteries was determined. Compared with control aortas, nifedipine treatment (n = 5) significantly reduced homologous 125I-tyramine cellobiose-LDL accumulation (control versus nifedipine: 45.93 +/- 4.3 versus 20.14 +/- 3.1 ng LDL per milligram dry weight x10(-3), p = 0.001) while the reduction of human LDL accumulation (n = 5) was not significant (49.1 +/- 6.1 versus 35.5 +/- 4.1 ng LDL per milligram dry weight x10(-3)). Aortic accumulation of orally administered 3Hcholesterol was also inhibited by nifedipine (352 +/- 34 versus 257 +/- 16 ng cholesterol per milligram dry weight x10(-3), n = 10, p = 0.022). These findings suggest a possible mechanism for the antiatherosclerotic effect of nifedipine. |