| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Intracellular cholesterol transport Fielding, C. J. and P. E. Fielding (1997), J Lipid Res 38(8): 1503-21. Abstract: Recent data on the roles of vesicle- and 'raft'-mediated pathways in intracellular free cholesterol (FC) transport are reviewed. Cholesterol internalized from plasma lipoproteins is transferred via endocytic vesicles to the trans-Golgi network (TGN), consistent with prior data indicating a key role for this organelle in protein and lipid sorting and transport. Newly synthesized and lipoprotein-derived FC are returned to the cell surface by a common raft-dependent pathway. Intracellular FC transport promotes the delivery of GPI-anchored proteins to the cell surface; it is also an additional mechanism to regulate cell FC content. Many peripheral cells express caveolin, an FC-binding protein localized to plasma membrane caveolae. FC delivery to cell surface caveolae is accelerated by caveolin. Caveolar FC becomes targeted to small, lipid-poor (prebeta-) high density lipoprotein particles. Caveolin may protect quiescent cells, regulating FC efflux more efficiently in response to changing medium lipoprotein concentrations. Overall, these recent findings suggest that cell FC content can be regulated at the levels of both influx and efflux, and indicate key roles for the TGN and in cells expressing caveolin, cell-surface caveolae. |
| Intracellular cholesterol transport Liscum, L. and N. J. Munn (1999), Biochim Biophys Acta 1438(1): 19-37. |
| Intracellular cholesterol transport Liscum, L. and N. K. Dahl (1992), J Lipid Res 33(9): 1239-54. Abstract: The intracellular movement of cholesterol in mammalian cells may involve complex pathways by which the sterol moves to various cellular sites and mediates transcriptional regulation, enzyme activation, and protein degradation. Current evidence indicates that there are three distinct pathways modulating intracellular cholesterol trafficking. The movement of endogenously synthesized cholesterol from the endoplasmic reticulum appears to be distinct from movement of exogenous, low density lipoprotein (LDL)-derived cholesterol to the plasma membrane. In addition, steroidogenic cells possess a third mechanism by which cholesterol is transported to the mitochondria to initiate steroid hormone synthesis. In this review, we have outlined the current knowledge of cholesterol transport mechanisms and pathways and have described approaches that may help define cholesterol trafficking mechanisms in molecular detail. The use of genetic and molecular biologic techniques can potentially reveal gene products that are involved in intracellular cholesterol transport and regulation as well as those that may secondarily affect this process. |
| Intracellular cholesterol transport Maxfield, F. R. and D. Wustner (2002), J Clin Invest 110(7): 891-8. |
| Intracellular cholesterol transport Soccio, R. E. and J. L. Breslow (2004), Arterioscler Thromb Vasc Biol 24(7): 1150-60. Abstract: Intracellular cholesterol transport is essential for the maintenance of cholesterol homeostasis. Many aspects of cholesterol metabolism are well-known, including its synthesis in the endoplasmic reticulum, its extracellular transport in plasma lipoproteins, its uptake by the low-density lipoprotein receptor, and its regulation of SREBP and LXR transcription factors. These fundamental pathways in cholesterol metabolism all rely on its proper intracellular distribution among subcellular organelles and the plasma membrane. Transport involving the ER and endosomes is essential for cholesterol synthesis, uptake, and esterification, whereas cholesterol catabolism by enzymes in mitochondria and ER generates steroids, bile acids, and oxysterols. Cholesterol is a highly hydrophobic lipid that requires specialized transport in the aqueous cytosol, involving either vesicles or nonvesicular mechanisms. The latter includes hydrophobic cavity transporters such as StAR-related lipid transfer (START) proteins. Molecular understanding of intracellular cholesterol trafficking has lagged somewhat behind other aspects of cholesterol metabolism, but recent advances have defined some transport pathways and candidate proteins. In this review, we discuss cholesterol transport among specific intracellular compartments, emphasizing the relevance of these pathways to cholesterol homeostasis. |
| Intracellular cholesterol transport and compartmentation Liscum, L. and K. W. Underwood (1995), J Biol Chem 270(26): 15443-6. |
| Intracellular cholesterol transport by NPC1/HE1 Ninomiya, H. (2004), Seikagaku 76(6): 571-7. |
| Intracellular cholesterol transport in synchronized human skin fibroblasts Fielding, C. J., A. Bist, et al. (1999), Biochemistry 38(8): 2506-13. Abstract: Normal human skin fibroblasts maintained in serum-containing medium were synchronized with aphidicolin. After removal of inhibitor, free cholesterol (FC) homeostasis was determined at intervals during the following cell cycle. FC mass per cell doubled following S-phase, and reached its maximum well before mitosis. This increase was mainly the result of stimulation of the rate of selective uptake of FC from medium lipoproteins, and reduction of FC efflux. Rates of cholesterol synthesis, endocytosis of intact low-density lipoprotein, and HDL receptor (CLA-1) activity were relatively low and little changed during the cell cycle. The expression of caveolin (structural protein of cell surface caveolae) and caveolar FC were decreased along with FC efflux. To test the hypothesis that regulation of caveolin expression could contribute to changes in FC efflux during cell division, cells were transfected with human caveolin cDNA, synchronized with aphidicolin, and then allowed to divide. In the transfected cells, caveolar FC and FC efflux were both increased. FC accumulation and entry into mitosis were markedly inhibited compared to controls. The contribution of transcriptional regulation to caveolin mRNA levels was determined with a 705 bp caveolin 5'-flanking sequence ligated to the pGL3 luciferase expression vector. Expression of the reporter gene was downregulated at S-phase of synchronized cells. Deletion of a hybrid E2F/ Sp1-like site between -139 and -150 bp abolished this downregulation. These data are consistent with a role for caveolin in cell cycle kinetics, which may be mediated, at least in part, at the transcriptional level. |
| Intracellular distribution and mobilization of unesterified cholesterol in adipocytes: triglyceride droplets are surrounded by cholesterol-rich ER-like surface layer structures Prattes, S., G. Horl, et al. (2000), J Cell Sci 113 (Pt 17): 2977-89. Abstract: In addition to their central role in triglyceride storage, fat cells are a primary depot of unesterified cholesterol (FC) in the body. In comparison, peripheral cells contain very little FC. This difference in adipocytes versus peripheral tissues is inconsistent with the current theory of cholesterol homeostasis. Attempting to resolve this discrepancy, we examined intracellular storage sites of FC in murine 3T3-F442A adipocytes. Using the cholesterol-binding antibiotic, filipin, in combination with high resolution fluorescence microscopy, intense fluorescent staining characteristically decorated the periphery of triglyceride droplets (TGD) as well as the plasma membrane (PM) of fat cells. Filipin-staining was not visible inside the lipid droplets. Purification of TGD by subcellular fractionation demonstrated that the rise in total FC content of adipocytes upon differentiation was attributable to an increase in TGD-FC, which contributed up to one third of the total cellular FC. The protein component of purified TGD from cultured adipocytes as well as from murine adipocytes obtained from fresh tissues contained the lumenal endoplasmic reticulum (ER) immunoglobulin binding protein (BiP) and the integral ER membrane protein calnexin. Efflux experiments using the extracellular FC acceptors (&bgr)-cyclodextrin or apolipoprotein A-I demonstrated that TGD-associated FC was releasable from TGD. Whereas FC efflux from adipocytes was unaffected in the presence of brefeldin A or monensin, the secretion of a control protein, lipoprotein lipase, was effectively reduced. In summary, our findings identify the TGD surface layer as primary intracellular storage site for FC within adipocytes. We suggest that the structural role of ER-resident proteins in this adipocyte TGD envelope has been previously neglected. Our findings support the suggestion that an ER-like structure, albeit of modified lipid composition, constitutes the lipid droplets' surface layer. Finally, the efflux process of FC from adipocytes upon extracellular stimulation with (beta)-cyclodextrin provides evidence for an energy-dependent intracellular trafficking route between the TGD-FC pool and the PM-FC sites which is distinct from the secretory pathway of proteins. |
| Intracellular liposomes and cholesterol deposits in chronic cholecystitis and biliary sludge Gilloteaux, J., D. Miller, et al. (2004), Ultrastruct Pathol 28(3): 123-36. Abstract: Ultrastructural study of a group of selected specimens of chronic cholecystitic gallbladders reveals cholecystocyte changes characterized by abraded and altered microvilli accompanied by mitochondrial damages in the apical regions as well as mucus accumulation with aggregated, angulated lysosomes and heterogeneous liposomes. These liposomes contain needle-like crystals, probably rich in cholesterol. Many fragments of cholecystocystes and damaged organelles or contents can be found in the biliary sludge. These data support previous reports suggesting that there is an association between cholecystitis and the presence of cholelithiasis, subsequent to the production of altered bile. The present data suggest that disintegrating, sloughed cholecystocyte contents also contribute to the bile sludge, a complex milieu enriched by lipids, cholesterol deposits, altered mucus due in part to changes in expression of apomucins. The instability of prolonged storage of such modified bile, caused and/or accompanied by other associated metabolic defects, including gallbladder sluggishness, would favor the nucleation and the enlargement of gallstones. Based on the aforementioned data, a comprehensive sequence for cholecystocyte ultrastructural alterations and pathologies is proposed, as a result of chronic cholecystitis. |
| Intracellular pH regulation of SV-40 virus transformed human MRC-5 fibroblasts and cell membrane cholesterol Ng, L. L., P. Delva, et al. (1993), Am J Physiol 264(4 Pt 1): C789-93. Abstract: Alterations in membrane cholesterol could affect the activity of various membrane transporters, including the Na(+)-H+ antiport. The effect of cellular cholesterol depletion (with phosphatidylcholine liposomes) and enrichment (with cholesterol and phosphatidylcholine liposomes) on cellular pH regulation was studied in SV-40 virus transformed human MRC-5 fibroblasts. Cellular cholesterol depletion led to activation of the Na(+)-H+ antiport by an increased maximal velocity (Vmax) of the transporter, with no changes in the apparent dissociation constant (Kd) or Hill coefficient for intracellular H+. Cholesterol enrichment had no effect on the activation of the Na(+)-H+ antiport by intracellular acidosis. However, activation of the Na(+)-H+ antiport by an osmotic stimulus was enhanced in cholesterol-depleted cells and reduced in cholesterol-enriched cells. Liposomes that had no effect on cellular cholesterol did not alter the activation of Na(+)-H+ antiport activity by intracellular acidosis or an osmotic stimulus. Thus in situ modification of cellular cholesterol altered Na(+)-H+ antiport activity differently depending on the type of activating stimulus. |
| Intracellular trafficking of cholesterol monitored with a cyclodextrin Neufeld, E. B., A. M. Cooney, et al. (1996), J Biol Chem 271(35): 21604-13. Abstract: The sterol binding agent 2-hydroxypropyl-beta-cyclodextrin is shown to be a convenient and useful experimental tool to probe intracellular pathways of cholesterol transport. Biochemical and cytochemical studies reveal that cyclodextrin specifically removes plasma membrane cholesterol. Depletion of plasma membrane sphingomyelin greatly accelerated cyclodextrin-mediated cholesterol removal. Cholesterol arriving at the plasma membrane from lysosomes and the endoplasmic reticulum was also removed by cyclodextrin. Cellular cholesterol esterification linked to the mobilization of cholesterol from lysosomes was strongly attenuated by cyclodextrin, suggesting that the major portion of endocytosed cholesterol is delivered from lysosomes to the endoplasmic reticulum via the plasma membrane. Evidence for translocation of lysosomal cholesterol to the endoplasmic reticulum by a plasma membrane-independent pathway is provided by the finding that cyclodextrin loses its ability to suppress esterification when plasma membrane sphingomyelin is depleted. The Golgi apparatus appears to play an active role in directing the relocation of lysosomal cholesterol to the plasma membrane since brefeldin A also abrogated cyclodextrin-mediated suppression of cholesterol esterification. Using cyclodextrin we further show that attenuated esterification of lysosomal cholesterol in Niemann-Pick C cells reflects defective translocation of cholesterol to the plasma membrane that may be linked to abnormal Golgi trafficking. |
| Intracellular trafficking of the free cholesterol derived from LDL cholesteryl ester is defective in vivo in Niemann-Pick C disease: insights on normal metabolism of HDL and LDL gained from the NP-C mutation Shamburek, R. D., P. G. Pentchev, et al. (1997), J Lipid Res 38(12): 2422-35. Abstract: Niemann-Pick C disease (NP-C) is a rare inborn error of metabolism with hepatic involvement and neurological sequelae that usually manifest in childhood. Although in vitro studies have shown that the lysosomal distribution of LDL-derived cholesterol is defective in cultured cells of NP-C subjects, no unusual characteristics mark the plasma lipoprotein profiles. We set out to determine whether anomalies exist in vivo in the cellular distribution of newly synthesized, HDL-derived or LDL-derived cholesterol under physiologic conditions in NP-C subjects. Three affected and three normal male subjects were administered 14Cmevalonate as a tracer of newly synthesized cholesterol and 3Hcholesteryl linoleate in either HDL or LDL to trace the distribution of lipoprotein-derived free cholesterol. The rate of appearance of free 14C- and free 3Hcholesterol in the plasma membrane was detected indirectly by monitoring their appearance in plasma and bile. The plasma disappearance of 3Hcholesteryl linoleate was slightly faster in NP-C subjects regardless of its lipoprotein origin. Appearance of free 14C cholesterol ill the plasma (and in bile) was essentially identical in normal and affected individuals as was the initial appearance of free 3Hcholesterol derived from HDL, observed before extensive exchange occurred of the 3Hcholesteryl linoleate among lipoproteins. In contrast, the rate of appearance of LDL-derived free 3Hcholesterol in the plasma membrane of NP-C subjects, as detected in plasma and bile, was retarded to a similar extent that LDL cholesterol metabolism was defective in cultured fibroblasts of these affected subjects. These findings show that intracellular distribution of both newly synthesized and HDL-derived cholesterol are essentially unperturbed by the NP-C mutation, and therefore occur by lysosomal-independent paths. In contrast, in NP-C there is defective trafficking of LDL-derived cholesterol to the plasma membrane in vivo as well as in vitro. The in vivo assay of intracellular cholesterol distribution developed herein should prove useful to quickly evaluate therapeutic interventions for NP-C. |
| Intracellular transport of low density lipoprotein derived free cholesterol begins at clathrin-coated pits and terminates at cell surface caveolae Fielding, P. E. and C. J. Fielding (1996), Biochemistry 35(47): 14932-8. Abstract: Free cholesterol (FC) is selectively internalized from low-density lipoprotein (LDL) by confluent fibroblast monolayers (Fielding & Fielding (1995) Biochemistry 34, 14237-14244). The kinetics of transport of LDL-derived 3H-FC within the cell were studied by density-gradient ultracentrifugal fractionation and in terms of the effects of inhibitors of endocytosis and intracellular transport. By these criteria, the initial uptake of LDL-FC was mediated by the cell-surface clathrin-coated pits. FC label then appeared in clathrin-coated dense vesicles. Uncoating of clathrin from these vesicles led to the appearance of label in a light density fraction and, subsequently, in an intermediate density fraction coincident with protein markers of the trans-Golgi network in these cells. 3H-FC was finally transported to the plasma membrane via a temperature-sensitive, probably microtubule-dependent pathway. These data are consistent with a role for the trans-Golgi network as an intermediate compartment in intracellular FC transport. They provide further evidence of a role for cell-surface caveolae in FC efflux. |
| Intracerebroventricular leptin regulates hepatic cholesterol metabolism Vanpatten, S., G. B. Karkanias, et al. (2004), Biochem J 379(Pt 2): 229-33. Abstract: To elucidate the control of hepatic cholesterol metabolism by leptin, rats were administered IV (intravenous) leptin, ICV (intracerebroventricular) leptin or saline. A single low dose of ICV leptin was as effective as a continuous IV infusion of high-dose leptin at decreasing the activities of 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7alpha-hydroxylase. These results indicate that the hepatic response to leptin is transduced via the central nervous system. |
| Intraclass correlation coefficients for cluster randomized trials in primary care: the cholesterol education and research trial (CEART) Parker, D. R., E. Evangelou, et al. (2005), Contemp Clin Trials 26(2): 260-7. Abstract: Cluster randomization trials are increasingly being used in primary care research. The main feature of these trials is that patients are nested within large clusters such as physician practices or communities and the intervention is applied to the cluster. This study design necessitates calculation of intraclass correlation coefficients in order to determine the required sample size. The purpose of this study is to determine intraclass correlation coefficients for a number of outcome measures at the primary care practice level. The CEART study is a randomized trial testing the effectiveness of translating ATP III guidelines into clinical practice, with primary care physician practices as the unit of randomization and patients as the unit of data collection. The intraclass correlation coefficient (ICC) was<0.02 and the design effect ranged from 1.0 to 2.3, respectively, for weight, total cholesterol, LDL, non-HDL, glucose, creatinine, and % at non-HDL goal. For smoking status, body mass index, systolic blood pressure, HDL cholesterol triglycerides, total cholesterol/HDL ratio and % at LDL goal, the ICC was 0.02-0.047 and the design effect was 2.6-4.1. The largest ICCs (0.05-0.12) and design effects (4.4-9.4) were found for height and diastolic blood pressure. These findings suggest that cluster randomization may substantially increase the sample size necessary to maintain adequate statistical power for selected outcomes such as diastolic blood pressure studies compared with simple randomization for most outcomes evaluated in this study where the design effect is small to moderate. Overall, the ICCs presented will be useful in calculating sample sizes at the primary care level. |
| Intracranial cholesterol granulomas Leel-Ossy, L., S. Barla, et al. (2002), Ideggyogy Sz 55(1-2): 5-14. Abstract: In the development of a cholesterol granuloma both cellular and vascular permeability factors have to be taken into consideration. It may arise as a special degradation product in a chronic cerebral infarct because of the partial insufficient activity of the macrophages. Consequently, the degradation of brain sphingolipids and other compounds does not follow the usual route of degradation and transportation by granular cells to the stage of neutral fat but the necrotic mass transforms into cholesterol esters. Cholesterol crystals produce an irritative effect to neighbouring tissues which may result in the formation of young fibroblasts with proliferative tendency in the vessel wall. Some of the fibroblasts take part in the proliferation of connective tissue, while the rest degenerate, producing more cholesterol or xanthomatous material. Inflammatory changes may also be associated with these lesions. The amount of cholesterol sometimes increases in the inner side of the thickening connective tissue layer. The final result may be an intracranial space occupying mass or it may end as a small cholesterol granuloma, as demonstrated in our incidental cases. By the time a granuloma has developed, the original vessel usually disappears completely, but sometimes remnants of vessels might prove the vascular origin. Other pathomechanisms should also be taken into consideration, such as a cholesterol embolus or anomalous vessel with a large cholesterol plaque in the wall. This also explains why trauma (hemorrhage, granulation), cholesterol embolus, inflammation, metabolic imbalance may predispose to the formation of a granuloma, as well as the hypercholesterolaemia. The nine cases demonstrate the significance of the intracranial granuloma from pathological, clinical and neurosurgical points of view. Such cases have not yet been reported in the national or international literature. |
| Intracranial cholesterol granulomas. Report of 2 cases Kujas, M., R. van Effenterre, et al. (1999), Ann Pathol 19(6): 536-9. Abstract: Two cases of cholesterolic granuloma, one intraorbital and the other of the petrous apex, are reported. The xanthogranulomatous and/or cystic process localized in the intracranial cavities or in the brain parenchyma are discussed. A simple topographical and histological classification is attempted in answer to a rather ambiguous terminology. |
| Intracranial coexistence of neurinoma with epidermoid cyst or cholesterol granuloma. Report of 2 cases Talacchi, A., F. Giorgiutti, et al. (1997), J Neurosurg Sci 41(2): 179-88. Abstract: The authors present 2 cases of a rare association of intracranial tumors of different cell types: neurinoma with epidermoid cyst, and neurinoma with cholesterol granuloma. The presenting symptoms resulted from neurinomas arising from the V and VIII cranial nerves, respectively. The diagnoses were achieved using Magnetic Resonance Images (MRI). The association of these rare lesions is discussed using recent literature pertaining to the coexistence of multiple brain tumors. |
| Intractable leg ulceration caused by cutaneous cholesterol embolism Davies, D. J. and K. Thurasingham (1992), Med J Aust 157(4): 267-8. Abstract: OBJECTIVE: To present a case of chronic intractable leg ulceration caused by cholesterol crystal embolism. CLINICAL FEATURES: A 76-year-old Caucasian male with a history of ischaemic heart disease had repeated hospital admissions for diagnosis and treatment of recurrent leg ulceration of more than three years' duration. INTERVENTION AND OUTCOME: Definitive diagnosis was made after the third biopsy when the specimen obtained included subcutaneous arteries. Complete healing occurred within three weeks of excision and a skin graft, and subsequent treatment which included systemic steroids. CONCLUSION: Cholesterol crystal embolism is probably an underdiagnosed cause of intractable leg ulceration and can be identified by a biopsy specimen which includes vessels in subcutaneous fat. Systemic steroids may be helpful in its treatment. |