| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
| First Page | Previous Page | Next Page | Last Page |
| Molecular mechanism of membrane pore formation with cholesterol binding cytolysin: streptolysin O and perfringolysin O Shimizu, T. and H. Hayashi (2001), Tanpakushitsu Kakusan Koso 46(4 Suppl): 532-9. |
| Molecular mechanism of reverse cholesterol transport Miida, T. (2001), Nippon Rinsho 59 Suppl 2: 463-7. |
| Molecular mechanism of reverse cholesterol transport: reaction of pre-beta-migrating high-density lipoprotein with plasma lecithin/cholesterol acyltransferase Nakamura, Y., L. Kotite, et al. (2004), Biochemistry 43(46): 14811-20. Abstract: A 70-75 kDa high-density lipoprotein (HDL) particle with pre-beta-electrophoretic migration (pre-beta(1)-HDL) has been identified in several studies as an early acceptor of cell-derived cholesterol. However, the further metabolism of this complex has not been determined. Here we sought to identify the mechanism by which cell-derived cholesterol was esterified and converted to mature HDL as part of reverse cholesterol transport (RCT). Human plasma selectively immunodepleted of pre-beta(1)-HDL was used to study factors regulating pre-beta(1)-HDL production. A major role for phospholipid transfer protein (PLTP) in the recycling of pre-beta(1)-HDL was identified. Cholesterol binding, esterification by lecithin/cholesterol acyltransferase (LCAT) and transfer by cholesteryl ester transfer protein (CETP) were measured using (3)H-cholesterol-labeled cell monolayers. LCAT bound to (3)H-free cholesterol (FC)-labeled pre-beta(1)-HDL generated cholesteryl esters at a rate much greater than the rest of HDL. The cholesteryl ester produced in pre-beta(1)-HDL in turn became the preferred substrate of CETP. Selective LCAT-mediated reactivity with pre-beta(1)-HDL represents a novel mechanism increasing the efficiency of RCT. |
| Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous focal glomerulosclerosis Vaziri, N. D., T. Sato, et al. (2003), Kidney Int 63(5): 1756-63. Abstract: BACKGROUND: Imai rats exhibit spontaneous focal glomerulosclerosis (FGS), which is marked by heavy proteinuria, severe hyperlipidemia, and progressive renal insufficiency beginning at 8 to 10 weeks of age. In an earlier study, we reported severe skeletal muscle and adipose tissue lipoprotein lipase, and very low-density lipoprotein (VLDL) receptor deficiencies, which account for elevated plasma VLDL and triglycerides in Imai rats at 34 weeks of age. In this study, we investigated key factors involved in cholesterol metabolism. METHODS: Male Imai and Sprague-Dawley control rats were fed a regular rat chow and observed from age 8 through 34 weeks. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase, low-density lipoprotein (LDL) receptor and acyl Co A:cholesterol acyltransferase (ACAT) were measured by Western blot and plasma lecithin:cholesterol acyltransferase (LCAT) protein was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: At 34 weeks of age, the Imai rats showed severe proteinuria, hypoalbuminemia, 60% reduction in glomerular filtration rate (GFR), elevated plasma total and LDL cholesterol and LDL/high-density lipoprotein (HDL) ratio. Imai rats showed a twofold elevation of hepatic HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, but no significant change in cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in cholesterol catabolism to bile acids. This was accompanied by and largely due to a threefold down-regulation of hepatic LDL receptor, which limits hepatic uptake of LDL; and a threefold up-regulation of hepatic ACAT (P < 0.01), which augments esterification of hepatocyte free cholesterol, thus, limiting cholesterol-mediated feedback regulation of cholesterol synthesis and catabolism. Moreover, plasma LCAT concentration was severely depressed (by fourfold) in Imai rats. This abnormality can impair HDL-mediated cholesterol transport from extrahepatic tissues to the liver. CONCLUSION: The study revealed marked abnormalities of the key proteins involved in regulation of hepatic cholesterol metabolism. These abnormalities can account for severe dysregulation of cholesterol metabolism in Imai rats with spontaneous FGS, which closely resembles FGS in humans. |
| Molecular mechanisms of cholesterol absorption and transport in the intestine Hui, D. Y. and P. N. Howles (2005), Semin Cell Dev Biol 16(2): 183-92. Abstract: Many enzymes and transport proteins participate in cholesterol absorption. This review summarizes recent results on several proteins that are important for each step of the cholesterol absorption pathway, including the important roles of: (i) pancreatic triglyceride lipase (PTL), carboxyl ester lipase (CEL), and ileal bile acid transporter in determining the rate of cholesterol absorption; (ii) ATP binding cassette (ABC) transporters and the Niemann-Pick C-1 like-1 (NPC1L1) protein as intestinal membrane gatekeepers for cholesterol efflux and influx; and (iii) intracellular membrane vesicles and transport proteins in lipid trafficking through intracellular compartments prior to lipoprotein assembly and secretion to plasma circulation. |
| Molecular mechanisms of cholesterol or homocysteine effect in the development of atherosclerosis: Role of vitamin E Kartal Ozer, N., Y. Negis, et al. (2003), Biofactors 19(1-2): 63-70. Abstract: The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that alpha-tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place via inhibition of protein kinase C activity. alpha-Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo. Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H2O2 independent pathway and accelerate the progression of atherosclerosis. The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis. |
| Molecular mechanisms of intracellular cholesterol transport Ikonen, E. (1997), Curr Opin Lipidol 8(2): 60-4. Abstract: Several examples in recent literature show that the molecular principles governing intracellular cholesterol transport are starting to emerge. Two previously cloned proteins were discovered to play a role in sterol transport of steroidogenic cells: the scavenger receptor BI as an HDL receptor and steroidogenic acute regulatory protein in the transport of cholesterol to mitochondria. Increasing evidence suggests the involvement of multidrug resistance proteins in sterol trafficking from the cell surface to the endoplasmic reticulum or across the plasma membrane. Specialized plasma membrane invaginations, caveolae, were implicated in cholesterol efflux, and the abundant caveolar protein, caveolin-1 which belongs to a newly discovered caveolin family of proteins, was shown to be a cholesterol-binding membrane protein. |
| Molecular mechanisms of reverse cholesterol transport Barter, P. J. and K. A. Rye (1996), Curr Opin Lipidol 7(2): 82-7. Abstract: The initial step of reverse cholesterol transport, the efflux of cell cholesterol into the extracellular fluid, has received much attention over the past year. Some studies have provided insights into the mechanism of cholesterol efflux and others have focused on the identity of the extracellular acceptors of cell cholesterol. Attention has also been directed towards the influence of HDL composition on the ability of these lipoproteins to accept cell cholesterol. There have been several studies addressing the importance of pre-beta-migrating HDL and of lipid-free apolipoproteins as acceptors of cell cholesterol. On the basis of these and earlier reports, a hypothetical cycle is proposed in which lipid-free apolipoprotein A-I dissociates from plasma HDL and transfers into the interstitial space where it acquires phospholipids and cholesterol from cells and becomes a discoidal HDL. Discoidal HDL transfer via lymphatics to the plasma where they are converted into mature HDL, thus completing the cycle. |
| Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling Gofflot, F., C. Hars, et al. (2003), Hum Mol Genet 12(10): 1187-98. Abstract: Human disorders caused by inborn errors of cholesterol biosynthesis are characterized by dysmorphogenesis of multiple organs. This includes limb malformations that are observed at high frequency in some disorders, such as the Smith-Lemli-Opitz syndrome, indicating a pivotal role of cholesterol in limb morphogenesis. Recently, it has been demonstrated that cholesterol can modulate the activity of the Hedgehog proteins, that act as morphogens to regulate the precise patterning of many embryonic structures, among which the developing limbs. To provide insight in the functions of cholesterol during limb development and in the potential role of Hedgehog signaling in the genesis of limb defects, we developed an in vivo rat model of cholesterol deficiency. We show here that treatment with Triparanol, a distal inhibitor of cholesterol biosynthesis, induced patterning defects of the autopod at high frequency, including pre-axial syndactyly and post-axial polydactyly, thus reproducing limb anomalies frequently observed in humans. Using in situ hybridization, we show that these malformations originate from a modification of Sonic Hedgehog signaling in the limb bud at 13 days post-coitum, leading to a deficiency of the anterior part of the limb. This deficiency results in an imbalance of Indian Hedgehog expression in the forming cartilage, ultimately leading to reduced interdigital apoptosis and syndactyly. Our study thus unravels the molecular mechanisms underlying the genesis of limb defects associated with cholesterol deficiency in rodents, and most probably in humans. |
| Molecular medicine. The cholesterol quartet Goldstein, J. L. and M. S. Brown (2001), Science 292(5520): 1310-2. |
| Molecular modelling study of the role of cholesterol in the stimulation of the oxytocin receptor Politowska, E., R. Kazmierkiewicz, et al. (2001), Acta Biochim Pol 48(1): 83-93. Abstract: Cholesterol, an integral component of membranes in Eucaryota, is a modifier of membrane properties. In vivo studies have demonstrated that cholesterol can also modulate activities of some G protein-coupled receptors (GPCRs), which are integral membrane proteins. This can result either from an effect of cholesterol on the membrane fluidity or from specific interactions of the membrane cholesterol with the receptor, as recently demonstrated for the cholecystokinin type beta (CCKRbeta) or the oxytocin receptor (OTR). Using molecular modelling, we studied conformational preferences of cholesterol and several of its analogues. Subsequently, we simulated the distributions of their preferred conformations around the surface of OTR, CCKRbeta and a chimeric oxytocin/cholecystokinin receptor. Consequently, we suggest residues on the surface of OTR which are potentially significant in the OTR/cholesterol interaction. |
| Molecular order and dynamics of phosphatidylcholine bilayer membranes in the presence of cholesterol, ergosterol and lanosterol: a comparative study using 2H-, 13C- and 31P-NMR spectroscopy Urbina, J. A., S. Pekerar, et al. (1995), Biochim Biophys Acta 1238(2): 163-76. Abstract: We report the results of a comparative study of the molecular order and dynamics of phosphatidylcholine (PC) bilayer membranes in the absence and presence of cholesterol, ergosterol and lanosterol, using deuterium (2H) nuclear magnetic resonance (NMR) of deuterated phospholipid molecules, in addition to solid state 13C and 31P-NMR. Using dimyristoylphosphatidylcholines (DMPCs) specifically labeled at positions 2', 3', 4', 6', 8', 10' and 12' of the sn-2 chain together with the perdeuterated 2-2H27DMPC derivative, the order profile for 9 of the 13 methylene groups of the sn-2 chain was established at 25 degrees C for DMPC, DMPC/cholesterol, DMPC/ergosterol and DMPC/lanosterol membranes, at a fixed sterol/phospholipid mol ratio of 30%, and in the presence of excess water. The overall ordering effects were found to be ergosterol > cholesterol >> lanosterol. Transverse relaxation (T2e) studies of these systems indicated that while for DMPC, DMPC/cholesterol and DMPC/ergosterol the relative relaxation rates were in qualitative agreement with models which assume cooperative motions of the bilayer molecules as the main relaxation mechanism, those in DMPC/lanosterol were anomalously high, suggesting alterations of lipid packing. Using dipalmitoylphosphatidylcholine (DPPC) deuterated at the trimethylammonium group of the choline moiety, we found that the differential ordering and motional effects induced by the sterols in the acyl chains were also reflected in the headgroup, both in the gel (L beta) and liquid-crystalline phases. 13C and 1H spin dynamics studies of these systems, including cross-polarization, rotating frame longitudinal relaxation and dipolar echo relaxation rates showed that the mobility of the different regions of the phospholipid molecules in the binary lipid systems were inversely correlated with the ordering effects induced by the sterols. A novel combination of C-D bond order parameters (obtained by 2H-NMR) and 13C-1H cross polarization rates confirmed these results. The effects of the same sterols at the same molar proportion on the unsaturated lipid 1-2H31palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (2H31-POPC) at 25 and 35 degrees C were different from those observed on DMPC and showed ordering effects which are largest for cholesterol, while ergosterol and lanosterol produced significantly smaller effects. Transverse relaxation studies indicate that while cholesterol does not perturb cooperative motions in POPC, both ergosterol and lanosterol do. Again, high-resolution solid state 13C-NMR studies support the conclusions of the 2H-NMR experiments.(ABSTRACT TRUNCATED AT 400 WORDS) |
| Molecular organization of cholesterol in polyunsaturated membranes: microdomain formation Brzustowicz, M. R., V. Cherezov, et al. (2002), Biophys J 82(1 Pt 1): 285-98. Abstract: The molecular organization of cholesterol in phospholipid bilayers composed of 1,2-diarachidonylphosphatidylcholine (20:4-20:4PC), 1-stearoyl-2-arachidonylphosphatidylcholine (18:0-20:4PC), and 20:4-20:4PC/18:0-20:4PC (1/1 mol) was investigated by solid-state (2)H NMR and by low- and wide-angle x-ray diffraction (XRD). On the basis of distinct quadrupolar powder patterns arising from 3 alpha-(2)H(1)cholesterol intercalated into the membrane and phase separated as solid, solubility chi(NMR)(chol) = 17 +/- 2 mol% and tilt angle alpha(0) = 25 +/- 1 degrees in 20:4-20:4PC were determined. The corresponding values in 18:0-20:4PC were chi (NMR)(chol) > or = 50 mol% and alpha(0) = 16 +/- 1 degrees. Cholesterol solubility determined by XRD was chi(NMR)(chol) = 15 +/- 2 mol% and chi(NMR)(chol) = 49 +/- 1 mol% for 20:4-20:4PC and 18:0-20:4PC, respectively. XRD experiments show that the solid sterol is monohydrate crystals presumably residing outside the bilayer. The (2)H NMR spectrum for equimolar 3 alpha-(2)H(1)cholesterol added to mixed 20:4-20:4PC/18:0-20:4PC (1/1 mol) membranes is consistent with segregation of cholesterol into 20:4-20:4PC and 18:0-20:4PC microdomains of <160 A in size that preserve the molecular organization of sterol in the individual phospholipid constituents. Our results demonstrate unambiguously that cholesterol has low affinity to polyunsaturated fatty acids and support hypotheses of lateral phase separation of membrane constituents into sterol-poor/polyunsaturated fatty acid-rich and sterol-rich/saturated fatty acid-rich microdomains. |
| Molecular organization of cholesterol in polyunsaturated phospholipid membranes: a solid state 2H NMR investigation Brzustowicz, M. R., W. Stillwell, et al. (1999), FEBS Lett 451(2): 197-202. Abstract: We compared the molecular organization of equimolar 3alpha-2H1cholesterol in 18:0-18:1PC (1-stearoyl-2-oleoylphosphatidylcholine), 18:0-22:6PC (1-stearoyl-2-docosahexaenoylphosphatidylcholine), 18:0-20:4PC (1-stearoyl-2-arachidonylphosphatidylcholine) and 20:4-20:4PC (1,2-diarachidonylphosphatidylcholine) bilayers by solid state 2H NMR. Essentially identical quadrupolar splittings (delta v(r) = 45 +/- 1 kHz) corresponding to the same molecular orientation characterized by tilt angle alpha0 = 16 +/- 1 degrees were measured in 18:0-18:1PC, 18:0-22:6PC and 18:0-20:4PC. A profound difference in molecular interaction with dipolyunsaturated 20:4-20:4PC, in contrast, is indicated for the sterol. Specifically, the tilt angle alpha0 = 22 +/- 1 degrees (derived from delta v(r) = 37 +/- 1 kHz) is greater and its membrane intercalation is only 15 mol%. |
| Molecular physiology of reverse cholesterol transport Fielding, C. J. and P. E. Fielding (1995), J Lipid Res 36(2): 211-28. Abstract: Reverse cholesterol transport (RCT) is the pathway by which peripheral cell cholesterol can be returned to the liver for catabolism. Evidence of specific functions for molecular structures within individual plasma lipoprotein species has rapidly accumulated from recent studies using molecular and cellular physiology techniques. The removal of cholesterol from cells, like its delivery, appears to be specific and well regulated. Although further research will be needed, RCT can now be understood in molecular terms. |
| Molecular processing of HDL by the liver during reverse cholesterol transport Mayes, P. A. and M. A. Mindham (1996), Z Gastroenterol 34 Suppl 3: 147-8. Abstract: 35S)-labelled HDL was prepared from the chyle of rats after feeding 35S)methionine/cysteine. It was added to the perfusate of isolated rat spleens, pre-labelled with 3H)cholesterol and perfused simultaneously with a rat liver. This system allowed the complete process of reverse cholesterol transport to take place while the uptake of individual HDL apolipoproteins and cholesterol by the liver was studied. In 3 h, uptake of apo C, A-IV and E was 24-59% whereas the uptake of apo A-I was negligible. 42% of the 3H)cholesterol entering the perfusate was taken up by the liver with 16% of the HDL cholesteryl ester mass. The results indicate that hepatic uptake of HDL cholesterol and cholesteryl ester is accompanied by some apolipoprotein uptake but not apo A-I. The apo A-I containing HDL particle is released back into the perfusate where it can return to extrahepatic tissues to take up more cholesterol. Further experiments in whole rats showed that human apo A-I (60 mg), when administered to rats i.v. with the 35S)HDL, displaced 35S) into the d > 1.250 density fraction of plasma. This trebled the apparent uptake of unassociated apo A-I into the kidney supporting the hypothesis that the kidney is the organ of destruction of apo A-I. |
| Molecular regulation of cholesterol biosynthesis: implications in carcinogenesis Singh, R. P., R. Kumar, et al. (2003), J Environ Pathol Toxicol Oncol 22(2): 75-92. Abstract: Cholesterol synthesis was demonstrated to be mandatory for cellular growth and serves to supply one of the necessary building blocks for new membranes demanded by dividing cells during growth. The mevalonate pathway, which is regulated through a finely tuned mechanism, is responsible mainly for cholesterol enrichment to cells. Among the various steps, the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) is the most critically regulated step catalyzed by HMG-CoA reductase. The ability of sterols to regulate both the transcriptional rates of the reductase gene and the degradative machinery for the reductase protein provides a multilevel system for controlling the expression of this enzyme. Much convincing evidence indicates that cells manifest a higher flux through the mevalonate pathway when proliferating than when they are in the cell cycle arrest condition; furthermore, tumors undergo deregulated cholesterogenesis mainly at the critical rate-controlling juncture (i.e., the reaction catalyzed by HMG-CoA reductase). The mevalonate component of the cholesterol biosynthesis plays a key role in controlling cell proliferation by generating prenyl intermediates, particularly farnesyl and geranyl-geranyl moieties. These isoprenoids covalently modify and thus modulate the biological activity of signal transducing proteins, such as that of the Ras superfamily. The prenylated Ras-mediated signal transduction pathway provides much of the molecular information needed to trigger cell proliferation. Therefore, depletion of mevalonate can block both the processing and the transforming activities of Ras, indicating that drugs such as lovastatin and compactin, which had previously been exploited for lowering cholesterol levels, may be useful chemotherapeutic agents for treating tumors harboring oncogenic Ras mutation. In addition, Ras prenylation, which provides much of the molecular information needed to trigger cell proliferation, represents an inviting target for the design of chemotherapeutic drugs that would interrupt such signaling events and arrest tumor cell proliferation. |
| Molecular structure of a novel cholesterol-responsive A subclass ABC transporter, ABCA9 Piehler, A., W. E. Kaminski, et al. (2002), Biochem Biophys Res Commun 295(2): 408-16. Abstract: We recently identified a novel ABC A subclass transporter, ABCA6, in human macrophages. Here, we report the molecular cloning of an additional ABC A subfamily transporter from macrophages denoted ABCA9. The identified coding sequence is 4.9 kb in size and codes for a 1624 amino acid protein product. In accordance with the proposed nomenclature, the novel transporter was designated ABCA9. The putative full-length ABC transporter polypeptide consists of two transmembrane domains and two nucleotide binding folds and thus conforms to the group of full-size ABC transporters. We identified alternative ABCA9 mRNA variants in human macrophages that predict the existence of three truncated forms of the novel transporter. Among the human ABC A subfamily transporters, ABCA9 exhibits the highest amino acid sequence homology with ABCA8 (72%) and ABCA6 (60%), respectively. The striking amino acid sequence similarity between these transporter molecules supports the notion that they represent an evolutionary more recently emerged subgroup within the family of ABC A transporters, which we refer to as "ABCA6-like transporters." ABCA9 mRNA is ubiquitously expressed with the highest mRNA levels in heart, brain, and fetal tissues. Analysis of the genomic structure revealed that the ABCA9 gene consists of 39 exons that are located within a genomic region of approximately 85 kb size on chromosome 17q24.2. In human macrophages, ABCA9 mRNA is induced during monocyte differentiation into macrophages and suppressed by cholesterol import indicating that ABCA9, like other known ABC A subfamily transporters, is a cholesterol-responsive gene. Based on this information, ABCA9 is likely involved in monocyte differentiation and macrophage lipid homeostasis. |
| Molecular studies on the role of dietary fat and cholesterol in breast cancer induction Archer, M. C., A. el-Sohemy, et al. (1997), Adv Exp Med Biol 422: 39-46. |
| Molecular-level organization of saturated and polyunsaturated fatty acids in a phosphatidylcholine bilayer containing cholesterol Pitman, M. C., F. Suits, et al. (2004), Biochemistry 43(49): 15318-28. Abstract: Cholesterol's preference for specific fatty acid chains is investigated at the atomic level in a 20 ns molecular dynamics computer simulation of a lipid bilayer membrane consisting of cholesterol and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (SDPC) in a 1:3 ratio. These simulations reproduce experimental measurements suggesting that cholesterol prefers to be solvated by saturated acyl chains and has a low affinity for polyunsaturated fatty acids. Analyses of the simulation trajectory provide a detailed picture of both the transverse and lateral structures of the lipid bilayer membrane, along with a description of lipid and cholesterol dynamics at high temporal resolution. Comparison with a previous simulation of a pure phospholipid bilayer allows an atomic-level description of the changes in membrane structure and dynamics resulting from incorporation of cholesterol. The observed differential cholesterol interactions with saturated and polyunsaturated lipids provide a mechanism for the formation of laterally inhomogeneous membranes; thus, the simulation provides molecular-level insight into the formation of lipid rafts. |