| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Modulation of pig kidney Na+/K+-ATPase activity by cholesterol: role of hydration Sotomayor, C. P., L. F. Aguilar, et al. (2000), Biochemistry 39(35): 10928-35. Abstract: Cholesterol is known to affect the activity of membrane-bound enzymes, including Na(+)/K(+)-ATPase. To gain insight into the mechanism of cholesterol's effect, we have used various hydrophobic fluorescent probes which insert into different regions of the membrane bilayer and report on the degree of hydration of their environment. Specifially, we have measured the generalized polarization of Laurdan and the lifetime of DPH and derivatives of DPH inserted into membranes from pig kidneys enriched in Na(+)/K(+)-ATPase. Spectral measurements were also carried out on these membranes after modification of their cholesterol content. The generalized polarization of Laurdan increased with increasing cholesterol, showing an abrupt modification at the native cholesterol content. The fluorescence lifetimes of DPH and the DPH derivatives were analyzed using a distribution model. The center value of these lifetime distributions and their widths also changed with increasing cholesterol. One DPH derivative, DPH-PC, showed a minimum value for the lifetime center at the native cholesterol concentration, whereas the other derivatives showed a maximum value for the lifetime center at that cholesterol concentration. DPH-PC is known to sense the protein-lipid interface, whereas the other derivatives sense the bulk lipid phase. These data suggest that hydration at the protein-lipid interface is maximal at the native cholesterol concentration as is the enzymatic activity. Hydration at the protein-lipid interface is therefore proposed to be required for activity. These results are in agreement with current models of membrane dynamics and thermodynamics of protein function. |
| Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters Jones, P. J., M. Raeini-Sarjaz, et al. (2000), J Lipid Res 41(5): 697-705. Abstract: It has been suggested that phytosterol and phytostanol esters possess similar cholesterol-lowering properties, however, whether mechanisms responsible are identical has not been addressed. To address this question, cholesterol plasma levels, absorption, biosynthesis, and turnover were measured in 15 hypercholesterolemic subjects consuming prepared diets each over 21 d using a cross-over design. Diets contained either i) margarine (M), ii) margarine with phytosterol esters (MSE) (1.84 g/d), or iii) margarine with phytostanol esters (MSA) (1.84 g/d). Cholesterol absorption was measured using the ratio of (13)Ccholesterol(oral):D(7)-cholesterol(IV); biosynthesis using D incorporation from D(2)O and turnover by D(7)-cholesterol(IV) decay rates. Plasma total cholesterol level at d 21/22 was lower (P < 0. 05) for MSE (13.4%) but not MSA (10.2%) versus M (6.0%) diets. Plasma low density lipoprotein-cholesterol (LDL-C) mean reductions at d 21/22 were larger (P < 0.05) for MSE (12.9%) and MSA (7.9%) compared with M (3.9%). Plasma TG and high density lipoprotein-cholesterol (HDL-C) levels did not differ across diets. Cholesterol absorption was reduced (P < 0.05) 36.2 and 25.9% at d 21 for MSE and MSA versus M, while cholesterol biosynthesis was reciprocally increased (P < 0.05) 53.3 and 37.8% for MSE and MSA versus M, respectively. Cholesterol turnover was not influenced by diet.These data indicate that plant sterol and stanol esters differentially lower circulating total and LDL cholesterol levels by suppression of cholesterol absorption in hypercholesterolemic subjects. |
| Modulation of plasma protein binding and in vivo liver cell uptake of phosphorothioate oligodeoxynucleotides by cholesterol conjugation Bijsterbosch, M. K., E. T. Rump, et al. (2000), Nucleic Acids Res 28(14): 2717-25. Abstract: Several studies have shown improved efficacy of cholesteryl-conjugated phosphorothioate antisense oligodeoxynucleotides. To gain insight into the mechanisms of the improved efficacy in vivo, we investigated the disposition of ISIS-9388, the 3'-cholesterol analog of the ICAM-1-specific phosphorothioate oligodeoxynucleotide ISIS-3082, in rats. Intravenously injected (3)HISIS-9388 was cleared from the circulation with a half-life of 49.9 +/- 2.2 min (ISIS-3082, 23.3 +/- 3.8 min). At 3 h after injection, the liver contained 63.7 +/- 3. 3% of the dose. Compared to ISIS-3082, the hepatic uptake of ISIS-9388 is approximately 2-fold higher. Endothelial, Kupffer and parenchymal cells accounted for 45.7 +/- 5.7, 33.0 +/- 5.9 and 21.3 +/- 2.6% of the liver uptake of (3)HISIS-9388, respectively, and intracellular concentrations of approximately 2, 75 and 50 microM, respectively, could be reached in these cells (1 mg/kg dose). Preinjection with polyinosinic acid or poly-adenylic acid reduced the hepatic uptake of (3)HISIS-9388, which suggests the involvement of (multiple) scavenger receptors. Size exclusion chromatography of mixtures of the oligonucleotides and rat plasma indicated that ISIS-9388 binds to a larger extent to high molecular weight proteins than ISIS-3082. Analysis by agarose gel electrophoresis indicated that ISIS-9388 binds more tightly to plasma proteins than ISIS-3082. The different interaction of the oligonucleotides with plasma proteins possibly explains their different dispositions. We conclude that cholesterol conjugation results in high accumulation of phosphorothioate oligodeoxynucleotides in various liver cell types, which is likely to be beneficial for antisense therapy of liver-associated diseases. |
| Modulation of regulatory factors involved in cholesterol metabolism in response to feeding of pravastatin- or cholesterol-supplemented diet in chickens Matsuyama, H., K. Sato, et al. (2005), Biochim Biophys Acta 1734(2): 136-42. Abstract: mRNA transcripts encoding multiple proteins from the cholesterol biosynthetic and uptake pathways in livers are controlled by sterol regulatory element binding protein-2 (SREBP-2), a membrane-bound mammalian transcription factor. The aims of the present study were to investigate whether SREBP-2 responds to plasma cholesterol levels and modulates expression of factors involved in the cholesterol metabolism of chickens. Supplementing the diets of chickens with 0.1% pravastatin, a drug used to control hypercholesterolemia, decreased plasma LDL-cholesterol concentrations. It also increased levels of the nuclear forms of SREBP-2 and increased gene expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) and low-density lipoprotein receptor (LDLr) in livers, relative to a control group. In contrast, feeding of 3% cholesterol-supplemented diet increased plasma total- and LDL-cholesterol concentrations but decreased levels of nuclear forms of SREBP-2 and reduced gene expression of HMGR and LDLr. However, the LDL-binding activities of chicken liver membranes were not affected by plasma cholesterol concentrations or by hepatic levels of the nuclear form of SREBP-2. LDL-binding proteins were detected as bands of 90 and 515 kDa on a ligand blot and the intensity of these bands was unaffected by pravastatin and cholesterol supplementation. These findings suggest that the cholesterol biosynthetic pathway is regulated by the nuclear form of SREBP-2 in chickens as well as in mammals, but that there may be species-specific differences in the regulatory mechanisms of hepatic cholesterol uptake. |
| Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol Howland, D. S., S. P. Trusko, et al. (1998), J Biol Chem 273(26): 16576-82. Abstract: The effects of dietary cholesterol on brain amyloid precursor protein (APP) processing were examined using an APP gene-targeted mouse, genetically humanized in the amyloid beta-peptide (Abeta) domain and expressing the Swedish familial Alzheimer's disease mutations. These mice express endogenous levels of APP holoprotein and abundant human Abeta. Increased dietary cholesterol led to significant reductions in brain levels of secreted APP derivatives, including sAPPalpha, sAPPbeta, Abeta1-40, and Abeta1-42, while having little to no effect on cell-associated species, including full-length APP and the COOH-terminal APP processing derivatives. The changes in levels of sAPP and Abeta in brain all were negatively correlated with serum cholesterol levels and levels of serum and brain apoE. These results demonstrate that secreted APP processing derivatives and Abeta can be modulated in the brain of an animal by diet and provide evidence that cholesterol plays a role in the modulation of APP processing in vivo. APP gene-targeted mice lacking apoE, also have high serum cholesterol levels but do not show alterations in APP processing, suggesting that effects of cholesterol on APP processing require the presence of apoE. |
| Modulation of sphingomyelinase-induced cholesterol esterification in fibroblasts, CaCo2 cells, macrophages and smooth muscle cells Stein, O., M. Ben-Naim, et al. (1992), Biochim Biophys Acta 1126(3): 291-7. Abstract: The present study has focused on three questions concerning the effect of sphingomyelinase on release of free cholesterol from the plasma membrane and its intracellular translocation: (i) Can one change the direction of the flow of cholesterol? (ii) Can one modulate the flow? (iii) May such a mechanism be relevant in atherogenesis? (i) The results obtained show that even in the presence of potent nonlipoprotein cholesterol acceptors in the medium, the intracellular flow of cholesterol is not reduced as measured by cholesterol esterification. Moreover, in sphingomyelinase-treated cells, cholesterol efflux in presence of nonlipoprotein acceptors was not enhanced even when intracellular esterification was inhibited. (ii) Modulation of the sphingomyelinase induced cholesterol flow can be obtained by 100 microM verapamil which reduces it. In human skin fibroblast, interference with the delivery of free cholesterol to its site of esterification was found in the presence of brefeldin A. (iii) Aortic smooth muscle cells in culture are sensitive to low concentrations of sphingomyelinase and the increase in esterified cholesterol is evident also after exposure to the enzyme for 24 h. The present results suggest that in the plasma membrane, free cholesterol bound to sphingomyelin may be in a compartment which renders it more available for transport to the cell interior than for efflux. In view of the sensitivity of aortic smooth muscle cells to sphingomyelinase, this mechanism for enhanced esterification of cholesterol could be relevant to the transformation of arterial smooth muscle cells into foam cells in the process of atherogenesis. |
| Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol Mitra, K., I. Ubarretxena-Belandia, et al. (2004), Proc Natl Acad Sci U S A 101(12): 4083-8. Abstract: A biological membrane is conceptualized as a system in which membrane proteins are naturally matched to the equilibrium thickness of the lipid bilayer. Cholesterol, in addition to lipid composition, has been suggested to be a major regulator of bilayer thickness in vivo because measurements in vitro have shown that cholesterol can increase the thickness of simple phospholipid/cholesterol bilayers. Using solution x-ray scattering, we have directly measured the average bilayer thickness of exocytic pathway membranes, which contain increasing amounts of cholesterol. The bilayer thickness of membranes of the endoplasmic reticulum, the Golgi, and the basolateral and apical plasma membranes, purified from rat hepatocytes, were determined to be 37.5 +/- 0.4 A, 39.5 +/- 0.4 A, 35.6 +/- 0.6 A, and 42.5 +/- 0.3 A, respectively. After cholesterol depletion using cyclodextrins, Golgi and apical plasma membranes retained their respective bilayer thicknesses whereas the bilayer thickness of the endoplasmic reticulum and the basolateral plasma membrane decreased by 1.0 A. Because cholesterol was shown to have a marginal effect on the thickness of these membranes, we measured whether membrane proteins could modulate thickness. Protein-depleted membranes demonstrated changes in thickness of up to 5 A, suggesting that (i) membrane proteins rather than cholesterol modulate the average bilayer thickness of eukaryotic cell membranes, and (ii) proteins and lipids are not naturally hydrophobically matched in some biological membranes. A marked effect of membrane proteins on the thickness of Escherichia coli cytoplasmic membranes, which do not contain cholesterol, was also observed, emphasizing the generality of our findings. |
| Modulation of the binding and endocytosis of concanavalin A by guinea pig keratinocytes: reversible antagonistic effects of cholesterol and phospholipid-liposomes Callaghan, T. M., P. Metezeau, et al. (1990), J Invest Dermatol 94(1): 58-64. Abstract: Alteration of guinea pig keratinocyte membrane microviscosities (eta) by liposomes of varying composition was determined by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. Measurements performed either with whole cell suspensions or Percoll-separated cell subpopulations, indicate a similar membrane microviscosity (eta = 3.37 poise +/- 10%) compared to those microviscosities reported for other cell types. Our findings show that treatment of guinea pig keratinocytes with liposomes composed of phospholipids results in a decreased membrane microviscosity (1.95 poise), whereas treatment of the cells with an emulsion of cholesterol hemisuccinate, or liposomes composed of cerebrosides, causes an increase in membrane microviscosity (3.85 poise and 5.55 poise +/- 10%, respectively). Changes in membrane fluidity had no significant effect on cell viability. A reduced membrane microviscosity resulted in a decrease in the binding of Concanavalin A to keratinocytes, whereas an increased microviscosity resulted in an increased binding of Concanavalin A. Furthermore, endocytosis of Concanavalin A bound to keratinocytes plasma membranes was not significantly affected by a reduced membrane microviscosity, whereas an increased membrane microviscosity completely blocked the endocytosis of Concanavalin A. Another novel observation was that membranes "fluidified" by phospholipid liposomes could be "rigidified" by treatment with cholesterol hemisuccinate and vice versa. Moreover, these alternate changes in membrane microviscosity resulted in simultaneous alternate changes in the binding of Concanavalin A to the keratinocyte surface. |
| Modulation of the cell membrane function by cholesterol and its relation to disease Mas Oliva, J. (1994), Gac Med Mex 130(6): 438-44; discussion 444-5. |
| Modulation of the multidrug resistance (MDR) system in the nematode Haemonchus contortus by changing cholesterol content: effects on resistance to anthelmintics Riou, M., F. Guegnard, et al. (2003), J Antimicrob Chemother 52(2): 180-7. Abstract: OBJECTIVES: The efficiency of the anthelmintics used to treat small domestic ruminants infected with nematodes is compromised by the emergence of resistant parasites. Both specific and non-specific mechanisms of resistance exist. The non-specific mechanisms involve multiple resistance phenomena and are dependent on the multidrug resistance (MDR) system, which is also responsible for the development of chemotherapy-resistant tumour cells. We showed previously that the system also exists in nematodes. Membrane 'pumps', known as P-glycoproteins (Pgp), are activated in the MDR system. The nature of the membrane, in particular the lipids, appears to condition the activity of the pumps. Thus, we studied the effects of cholesterol on drug transport activity in the nematode Haemonchus contortus. MATERIALS AND METHODS: We used methyl-beta-cyclodextrin to carry out cholesterol depletion and cholesterol loading experiments. The resulting changes in resistance were estimated by measuring changes in drug transport (a) by means of in vitro egg hatch assays in the presence of a benzimidazole anthelmintic, thiabendazole and (b) by measuring the transport of rhodamine 123 (R123), a specific substrate of Pgp. We used biochemical assays to estimate the cholesterol concentration in the parasites. RESULTS: Changes in the cholesterol content induced changes in anthelmintic resistance; cholesterol depletion gave increased resistance and cholesterol loading gave decreased resistance. These changes also altered the transport of R123. CONCLUSION: Cholesterol depletion or cholesterol loading allow modulation of xenobiotic resistance in nematode eggs as they do in tumour cells. The effect appears to be correlated with changes in the function of membrane P-glycoproteins. The lipid environment thus influences the nematode Pgp activity. |
| Modulation of the positional specificity of lecithin-cholesterol acyltransferase by the acyl group composition of its phosphatidylcholine substrate: role of the sn-1-acyl group Liu, M., V. S. Subramanian, et al. (1998), Biochemistry 37(39): 13626-33. Abstract: Human lecithin-cholesterol acyltransferase (LCAT), which is normally specific for the sn-2 position of phosphatidylcholine (PC), derives a significant percentage of acyl groups from the sn-1 position, when sn-2 is occupied by 18:0, 20:4, or 22:6. We investigated the relative importance of the two acyl groups of PC in determining the positional specificity by first analyzing the cholesteryl esters formed in the presence of symmetric PCs labeled at sn-2. Both human and rat LCATs transferred exclusively the sn-2-acyl group from all symmetric PCs, including 18:0-18:0, and 20:4-20:4, showing that the presence of these fatty acids at sn-2 does not automatically alter the positional specificity. The role of the sn-1-acyl group was then tested by using PCs containing 20:4 or 18:0 at sn-2 and fatty acids of various chain lengths and unsaturation at sn-1. With 20:4 at sn-2 and saturated fatty acids of various chain lengths at sn-1, human and rat LCATs derived, respectively, 5-72% and 1-20% of the total acyl groups from the sn-1 position. However, the chain length of the sn-1-acyl did not correlate with its utilization by either enzyme. Various unsaturated fatty acids at sn-1 also were transferred by human LCAT at a higher rate (5-75% of total) than they were transferred by rat LCAT (0-21%). With sn-2-18:0 PCs, however, rat LCAT exhibited greater alteration in positional specificity (30-95% from sn-1) than human LCAT (15-83% from sn-1). These results show that while the primary determinant of positional specificity is the sn-2-acyl group of PC, the structure of sn-1-acyl significantly modifies it. |
| Modulation of the substrate specificity of the mammalian phosphatidylinositol 3-kinase by cholesterol sulfate and sulfatide Woscholski, R., T. Kodaki, et al. (1995), Biochemistry 34(36): 11489-93. Abstract: The substrate specificity of the purified, mammalian phosphatidylinositol 3-kinase is subject to modulation by detergents, which are able to switch substrate specificity in vitro in favor of PtdInsP2. This effect of the detergents is due to an activation of the phosphatidylinositol biphosphate 3-kinase activity, while the phosphatidylinositol 3-kinase activity is inhibited. The selective inhibition of the phosphatidylinositol 3-kinase activity (p110 alpha/p85 alpha) is shown here also to be observed by employing cholesterol sulfate or sulfatide at low micromolar concentrations, whereas cholesterol and androsterone sulfate fail to inhibit. These naturally occurring sulfated lipids have at these concentrations no effect on the phosphatidylinositol bisphosphate 3-kinase activity but inhibit the manganese-dependent intrinsic protein kinase activity, thus switching substrate specificity toward the more highly phosphorylated inositol lipids. Cholesterol sulfate and sulfatide inhibit the free catalytic subunit p110 alpha but fail to inhibit the homologous phosphatidylinositol 3-kinase from Saccharomyces cerevisiae (Vps34p), suggesting that these sulfated lipids act specifically on the mammalian phosphatidylinositol 3-kinase. Consistent with this specificity, the regulatory subunit (p85), which is not conserved in the yeast enzyme, is found to play an important role for the affinity of these inhibitors. The implications for the phosphatidylinositol 3-kinase activity in vivo are discussed. |
| Modulation of THP-1 macrophage and cholesterol-loaded foam cell apolipoprotein E levels by glycosphingolipids Garner, B., H. R. Mellor, et al. (2002), Biochem Biophys Res Commun 290(5): 1361-7. Abstract: Macrophages synthesize and secrete apolipoprotein E (apoE) constitutively. This process is upregulated under conditions of cholesterol loading. The response to cholesterol is antiatherogenic as it is believed to promote cholesterol efflux from the artery wall. The concentration of lactosyl ceramide (LacCer), a glycosphingolipid recently discovered to regulate cellular signaling, proliferation, and expression of adhesion molecules, is also increased in atherosclerotic tissues. Here we have investigated the effect of exogenous LacCer on macrophage apoE levels. We show that increasing macrophage LacCer levels sevenfold led to reductions in cellular and secreted apoE (15 and 30%, respectively, over a 24-h period) as determined by enzyme-linked immunosorbent assay. A similar effect was also induced by glucosyl ceramide (GlcCer) but not by ganglioside species. When macrophages were converted to cholesterol-loaded foam cells by incubation with acetylated LDL, the resulting increase in cellular apoE levels was inhibited by 26% when the cells were subsequently enriched with LacCer. After metabolic labeling of cellular glycosphingolipids with 14Cpalmitate, we also discovered that high-density lipoprotein (HDL) stimulates the efflux of glycosphingolipids from foam cells. These data imply that LacCer and GlcCer may be proatherogenic due to the suppression of macrophage apoE production. Furthermore, the efflux of glycosphingolipids from macrophage foam cells to HDL could indicate a potential pathway for their removal from the artery wall and subsequent delivery to the liver. |
| Modulatory actions of Mystus gonadotropin on gamma-BHC-induced histological changes, cholesterol, and sex steroid levels in Heteropneustes fossilis Singh, P. B., D. E. Kime, et al. (1993), Ecotoxicol Environ Saf 25(2): 141-53. Abstract: Female specimens of Heteropneustes fossilis were exposed to a sublethal concentration of the organochlorine agricultural pesticide gamma-BHC (16 mg liter-1) for 4 weeks during the reproductively active preparatory and prespawning phases of the annual reproductive cycle. The effects of gamma-BHC on the gonadosomatic index (GSI) and on the histological changes in ovary, cholesterol-free cholesterol (CF), esterified cholesterol (CE), and the sex steroids testosterone-estradiol-17 beta, and 17 alpha-hydroxyprogesterone in plasma and ovary were monitored. Mystus gonadotropin (mGTH) was administered along with gamma-BHC exposure during the preparatory and prespawning phases. gamma-BHC decreases GSI during both phases; however, simultaneous administration of mGTH recovered the effect. gamma-BHC exposure caused inhibition of ovarian growth, resulting in a large number of stage I oocytes and few stage II oocytes, while at higher doses, mGTH reversed the impact of gamma-BHC, and a large number of stage III and vitellogenic oocytes were recorded. This pesticide also inhibited deesterification of CE to CF. Additionally, it impaired ovarian steroidogenesis and secretion of steroids into plasma. Lower doses of mGTH (0.1 and 1.0 microgram/fish) were ineffective in modulating the impact of gamma-BHC on lipids and steroids. However, higher doses (10 and 20 micrograms/fish) effectively revoked the impact of gamma-BHC, routed through the hypothalamo-hypophyseal-ovarian axis and directly upon the ovary. |
| Moisture content and particle size of dehydrated egg yolk affect lipid and cholesterol extraction using supercritical carbon dioxide Froning, G. W., R. L. Wehling, et al. (1998), Poult Sci 77(11): 1718-22. Abstract: Egg yolk was spray-dried under conditions to produce a small particle size powder and a large particle size powder. Particle size was determined using a Nikon Optiophot microscope. Spray-dried egg yolk was also adjusted to various moisture levels as follows: control (2 to 4% moisture), 7% moisture, and 12% moisture. Supercritical carbon dioxide extraction (SCE) of each of these moisture treatments at 45 C/306 atm using 30 g CO2/g of sample was completed. For the particle size study, 45 g CO2/g of sample at 45 C/306 atm was utilized. Particle size exhibited a significant effect on cholesterol and lipids extracted using SCE. As moisture content of dried egg yolk increased to 7%, there was a significant increase in lipids extracted using supercritical carbon dioxide. Moisture content had no significant effect on cholesterol extraction. After extracting SCE higher moisture spray-dried egg yolk, sponge cake volume was significantly reduced compared to that of the control. The reduced sponge cake volume may be due to protein denaturation. |
| Molasses increases HDL cholesterol in rats research note Schlegelmilch, U., C. Brandsch, et al. (2005), Int J Vitam Nutr Res 75(3): 211-7. Abstract: Two experiments were conducted to determine whether molasses might exert effects on serum lipoproteins. In experiment 1, 24 rats were divided into two groups and fed diets containing liquid molasses from sugar beet or sucrose (7.71 g of molasses dry matter or sucrose per kg of diet). The second experiment included four groups of rats (n = l2/group) and was conducted in a bifactorial design, with the factors being molasses (non-supplementation vs. supplementation of 77.1 g of molasses dry matter per kg of diet at the expense of sucrose) and dietary cholesterol (0 vs. 5 g/kg diet). In experiment 1, the ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol concentration tended to be lower in rats fed the molasses diet than in rats fed the control diet (p < 0.15). In experiment 2, rats fed the molasses diet had higher concentrations of HDL cholesterol (+ 26%) than control rats fed diets without molasses (p < 0.05). This effect was independent of the dietary cholesterol concentration. Concentrations of cholesterol in LDL, very low-density lipoprotein (VLDL), and liver as well as concentrations of triacylglycerols in plasma and liver remained unaffected by molasses in both experiments. In conclusion, the results of this study suggest that supplementation of molasses is effective at raising HDL cholesterol levels in rats. |
| Molecular aspects in feedback regulation of gene expression by cholesterol in mammalian cells Osborne, T. F. and V. J. LaMorte (1998), Methods 16(1): 42-8. Abstract: Intracellular cholesterol balance is maintained by a tight feedback mechanism that prevents the overaccumulation of cholesterol to cytotoxic levels. This is achieved through the coordinate regulation of genes of cholesterol uptake and biosynthesis by the sterol regulatory element binding proteins (SREBPs). The SREBPs are synthesized as membrane bound precursors that are released from their membrane tether when the cell needs new cholesterol. In the present article we present a model for how the cholesterol uptake pathway may be activated before the biosynthetic pathway to prevent wasting cellular energy and carbon on unneeded synthesis. Then we introduce a system for analyzing the differential localization and cellular trafficking of the different SREBP isoforms that can be performed over time in living cells. |
| Molecular basis of cholesterol feedback lesion in CNS tumours Kaul, D. and V. K. Khosla (2000), Neurol India 48(2): 174-7. Abstract: An important feature of malignant transformation of tumours is the loss of cholesterol feedback inhibition mechanism (cholesterol-feedback lesion) that regulates mevalonate pathway recognized to play a crucial role in cellular growth, death and differentiation. Recently, it was shown that Receptor-C(k)-dependent signalling regulates genes involved in maintaining cellular cholesterol homeostasis through a transcription factor sterol response element binding protein (SREBP) having affinity for sterol regulatory element (SRE) present in the promoter region of these genes. The present study revealed that CNS tumours exhibit overexpression of Receptor-C(k) gene product which was accompanied by their inability to express SREBP gene product and this phenomenon has the inherent capacity to initiate the cholesterol feedback lesion in these tumours. Based upon these and our earlier studies, we propose for the first time that this loss of cholesterol feedback control may be responsible for the initiation of these tumours. |
| Molecular basis of cholesterol homeostasis: lessons from Tangier disease and ABCA1 Oram, J. F. (2002), Trends Mol Med 8(4): 168-73. Abstract: High-density lipoproteins (HDLs) play a role in transporting cholesterol from peripheral tissues to the liver for elimination from the body. Two hallmarks of cardiovascular disease are the presence of sterol-laden macrophages in the artery wall and reduced plasma HDL levels. A cell-membrane protein called ABCA1 mediates the secretion of excess cholesterol from cells into the HDL metabolic pathway. Mutations in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome characterized by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Because of its ability to deplete macrophages of cholesterol and to raise plasma HDL levels, ABCA1 has become a promising therapeutic target for preventing cardiovascular disease. |
| Molecular basis of reverse cholesterol transport Wu, X. W. and M. D. Fu (1998), Sheng Li Ke Xue Jin Zhan 29(4): 361-3. |