| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The management of cholesterol in coronary heart disease risk reduction Woodhead, G. A. (1996), Nurse Pract 21(9): 45, 48, 51-3. Abstract: Coronary heart disease remains the number one cause of death in the American population. The Framingham Heart Study and other epidemiologic studies have demonstrated a direct relationship between elevated total and low-density lipoprotein cholesterol in the development of cardiovascular disease. This article focuses on secondary prevention, demonstrating that decreased cholesterol has a wide range of benefits in patients with cardiovascular disease. Emphasis is placed on the Scandinavian Simvastatin Survival Study which reported a 30% reduction of total mortality in a population of 4,444 patients with coronary heart disease who were treated with an HMG-CoA reductase inhibitor. The National Cholesterol Education Program guidelines for cholesterol risk reduction are reviewed. The impact of the health care provider as related to adherence and medication is discussed. Outcome issues of cost-effectiveness and resource utilization relating to cholesterol reduction are emphasized. |
| The mast cell--a potential link between inflammation and cellular cholesterol deposition in atherogenesis Kovanen, P. T. (1993), Eur Heart J 14 Suppl K: 105-17. Abstract: Mast cells are present in the arterial intima, the site of atherogenesis. In fatty streaks (the initial stage of atherogenesis) some of these cells are detected in the close vicinity of cholesterol-loaded macrophage foam cells. To ascertain whether mast cells could be involved in the formation of foam cells, a model system was developed in which isolated rat serosal mast cells were incubated with mouse peritoneal macrophages in a medium enriched with either low density lipoproteins (LDL) or high density lipoproteins (HDL3). Stimulation of the mast cells was found to induce 50-fold enhancement of LDL uptake by the macrophages. When stimulated, mast cells exocytose their secretory granules, which lose their membranes in the process. The granules then come in contact with the medium, which dissolves their histamine, a fraction of their heparin proteoglycans and all their chondroitin sulphate proteoglycans, leaving insoluble 'granule remnants'. These remnants consist of neutral proteases embedded in a heparin proteoglycan matrix. Some of the LDL particles in the incubation medium bind to this matrix, become degraded by the matrix-bound proteases, and fuse into larger particles on the surfaces of the remnants. These LDL particles are ingested by the macrophages as they phagocytose the remnants. Simultaneously, the soluble heparin proteoglycans interact with other LDL particles, forming insoluble complexes which are also phagocytosed by the macrophages. Cholesterol from the phagocytosed LDL particles ultimately becomes esterified in the macrophages, with formation of foam cells. In addition, mast cells block the removal of cholesterol from the foam cells: the remnant enzymes proteolyse HDL particles, so lessening their ability to induce efflux of cholesterol from the foam cells. These observations suggest that mast cells play an active role in the intracellular deposition of cholesteryl esters that is characteristic of early atherosclerotic lesions. |
| The mechanism of comparable serum cholesterol lowering effects of pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, between once- and twice-daily treatment regimens in beagle dogs and rabbits Fujioka, T., F. Nara, et al. (1996), Jpn J Pharmacol 70(4): 329-35. Abstract: In dogs, no significant difference in the reduction of serum cholesterol was observed among three dosing regimens of pravastatin: once in the morning (3 mg/kg), once in the evening (3 mg/kg), and twice-daily (1.5 mg/kg x 2) for 21 days. In rabbits, pravastatin was administered at a dose of 50 mg/kg once-daily given in the evening or 25 mg/kg twice-daily for 14 days; the respective serum and liver cholesterol levels were decreased by 41% and 7% in the once-daily dosing and by 51% and 11% in the twice-daily dosing. The amount of low density lipoprotein (LDL) receptor protein was increased 1.2-1.3-fold (P < 0.05) by both treatments, and no significant difference was noted between these treatment regimens. In addition, there was no significant difference in the extent of up-regulated LDL receptor protein between once-daily dosing in the evening and once-daily dosing in the morning. In the experiments with rabbit hepatocytes, the up-regulated LDL receptor activity induced by preincubation with pravastatin was retained even 24 hr after the removal of pravastatin. These results suggest that the comparable efficacy of pravastatin between once- and twice-daily treatment could be explained by retention of up-regulated LDL receptor activity for more than 24 hr in vitro and in vivo. |
| The mechanism of pore assembly for a cholesterol-dependent cytolysin: formation of a large prepore complex precedes the insertion of the transmembrane beta-hairpins Shepard, L. A., O. Shatursky, et al. (2000), Biochemistry 39(33): 10284-93. Abstract: Perfringolysin O (PFO) is a member of the cholesterol-dependent cytolysin (CDC) family of membrane-penetrating toxins. The CDCs form large homooligomers (estimated to be comprised of up to 50 CDC monomers) that are responsible for generating a large pore in cholesterol-containing membranes of eukaryotic cells. The assembly of the PFO cytolytic complex was examined to determine whether it forms an oligomeric prepore complex on the membrane prior to the insertion of its membrane-spanning beta-sheet. A PFO oligomeric complex was formed on liposomes at both 4 degrees C and 37 degrees C and shown by SDS-agarose gel electrophoresis to be comprised of a large, comparatively homogeneous complex instead of a distribution of oligomer sizes. At low temperature, the processes of oligomerization and membrane insertion could be resolved, and PFO was found to form an oligomer without significant membrane insertion of its beta-hairpins. Furthermore, PFO was found to increase the ion conductivity through a planar bilayer by large and discrete stepwise changes in conductance that are consistent with the insertion of a preassembled pore complex into the bilayer. The combined results of these analyses strongly support the hypothesis that PFO forms a large oligomeric prepore complex on the membrane surface prior to the insertion of its transmembrane beta-sheet. |
| The mechanism underlying the hypocholesterolemic effect of chronic fish oil feeding in rats is not due to increased excretion of dietary cholesterol Bravo, E., A. Cantafora, et al. (1998), Atherosclerosis 139(2): 253-63. Abstract: The role of the excretion of dietary cholesterol in the hypocholesterolaemic effect of chronic fish oil feeding in rats was investigated. The hepatic uptake and processing of 3Hcholesterol carried in chylomicrons derived from fish oil was studied in vivo in rats fed a low fat diet or a diet supplemented with fish oil for 21 days. In addition, the effects of the fish oil diet on cholesterol esterification, cholesteryl ester hydrolysis, bile acid synthesis and biliary lipid secretion were determined. In rats fed the fish oil as compared to the low fat diet, the uptake of 3Hcholesterol from the blood and its secretion into bile as bile acids was significantly slower, and this was entirely due to a decrease in the bile acid fraction. Biliary bile acid mass secretion was unchanged by fish oil feeding, while biliary cholesterol and phospholipid secretion was increased. No significant differences were observed either in the expression of mRNA for cholesterol 7alpha hydroxylase or the secretion of bile acids into bile after 20 h biliary drainage between the fish oil and low fat diet groups, suggesting that bile acid synthesis is not affected. These results indicate that the access of chylomicron cholesterol to the hepatic substrate pool for bile acid formation is decreased in the fish oil fed rats, and this, together with its slower uptake from the blood, accounts for the retardation of its excretion via the bile. Thus, the hypocholesterolemic effect of dietary fish oil in rats is not due to more rapid metabolism of cholesterol originating from the diet. |
| The medical cost of high serum cholesterol in Harris County, Texas Chenoweth, D. (2004), Tex Med 100(5): 50-3. Abstract: High serum cholesterol levels are common among Texans, especially in the greater Houston metropolitan area (Harris County) where such levels are almost 50% higher than the national norm. By using actual medical care claims and cost data, an analysis was conducted to determine the direct medical care cost of high serum cholesterol tied to selected cardiovascular conditions in Harris County. As part of conducting the analysis, Health Management Associates obtained prevalence rates of Harris County residents with elevated cholesterol levels, actual inpatient cardiovascular claims and costs, and estimated outpatient cardiovascular claims and costs. The financial cost analysis of high cholesterol revealed that more than 25 million dollars was spent alone on selected cardiovascular conditions. This estimate is conservative because it did not factor in all types of cardiovascular claims associated with high serum cholesterol, did not factor in other (noncardiovascular) claims that may be associated with high serum cholesterol, and did not include indirect costs such as absenteeism, lost productivity, and medication costs associated with the selected conditions. As Harris County is home to approximately 1 of every 5 adults in Texas, extrapolating the county's direct costs for high serum cholesterol to the entire state would translate into a direct medical care tab of more than 120 million dollars. |
| The Mediterranean diet improves the profile of male smokers compared with the diet recommended by the American Cholesterol Program (NCEP-I) Sanchez, E., S. Jansen, et al. (1999), Med Clin (Barc) 112(6): 206-10. Abstract: BACKGROUND: A study of the effect of smokers' diets on their atherogenic lipidic profile. SUBJECTS AND METHODS: 41 healthy males (32 non-smokers and 9 smokers) consumed consecutively a diet low in fat and rich in carbohydrates (28% total fat content < 10% saturated fats, and 57% carbohydrates), and a diet rich in monounsaturated fatty acids (38% total fat content with 22% monounsaturated fats). At the end of each dietary period, adhesion was confirmed by quantification of LDL cholesterol esters, plasma lipids and insulin levels. RESULTS: There were no significant differences between the age or the body mass of the groups of smokers or non-smokers. After both diets tobacco was found to have a significant effect on triglyceride levels (p < 0.0007), HDLc (p < 0.007), apo A-I (p < 0.02) and the LDLc/HDLc ratio (p < 0.005), revealing an interaction between diet and both HDLc levels (p < 0.004) and LDLc/HDLc ratios (p < 0.003). With the low fat and high monounsaturated fatty acid content diets smokers presented higher triglyceride levels (both with p < 0.0002) and LDLc/HDLc ratios (p < 0.0002 and p < 0.05, respectively) and lower levels of apo A-I (p < 0.002 and p < 0.004, respectively). However, in smokers the HDLc levels were only reduced after the low fat diet (p < 0.0003) and after the diet with a high monounsaturated fat content there was a rise in HDLc levels (p < 0.02) and a drop in the LDLc/HDLc ratio (p < 0.005) compared to the group of non-smokers. There were no significant differences in the insulin levels between groups. CONCLUSION: The atherogenic lipidic profile of smokers is due to an effect of tobacco on the lipidic metabolism. This atherogenic profile is accentuated with a low fat diet rich in carbohydrates and can be rectified to some degree with a diet with a high monounsaturated fatty acid content. |
| The membrane lipid cholesterol modulates anesthetic actions on a human brain ion channel Rehberg, B., B. W. Urban, et al. (1995), Anesthesiology 82(3): 749-58. Abstract: BACKGROUND: Molecular theories of general anesthesia often are divided into two categories: (1) Anesthetics may bind specifically to proteins, such as ionic channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane. Recent studies have provided evidence that anesthetics can bind to proteins and modify their function directly, bringing into question the role of the membrane in anesthetic interactions. To reexamine the role of membrane lipids in anesthetic interactions, an experimental approach was used in which the membrane lipid composition could be systematically altered and the impact on anesthetic interactions with potential targets examined. METHODS: Sodium channels from human brain cortex were incorporated into planar lipid bilayers with increasing cholesterol content. The anesthetic suppression of these channels by pentobarbital was quantitatively examined by single channel measurements under voltage-clamp conditions. RESULTS: Changes in cholesterol content had no effect on measured channel properties in the absence of anesthetic. In the presence of pentobarbital, however, cholesterol inhibited anesthetic suppression of channel ionic currents, with 1.9% (weight/weight, corresponding to 3.5 mol%) cholesterol decreasing anesthetic suppression of sodium channels by half. CONCLUSIONS: These results support a critical role for the lipid membrane in some anesthetic actions and further indicate that differences in lipid composition must be considered in the interpretation of results when comparing the anesthetic potencies of potential targets in model systems. |
| The membrane-permeabilizing effect of avenacin A-1 involves the reorganization of bilayer cholesterol Armah, C. N., A. R. Mackie, et al. (1999), Biophys J 76(1 Pt 1): 281-90. Abstract: Avenacin A-1 is a member of a group of naturally occurring compounds called saponins. It is found in oat plants, where it protects against fungal pathogens. A combined electrical and optical chamber was used to determine the interaction of avenacin A-1 with Montal-Mueller planar lipid bilayers. This system allowed simultaneous measurement of the effect of avenacin A-1 on the fluorescence and lateral diffusion of a fluorescent lipid probe and permeability of the planar lipid bilayer. As expected, cholesterol was required for avenacin A-1-induced bilayer permeabilization. The planar lipid bilayers were also challenged with monodeglucosyl, bis-deglucosyl, and aglycone derivatives of avenacin A-1. The results show that the permeabilizing activity of the native avenacin A-1 was completely abolished after one, two, or all three sugar residues are hydrolyzed (monodeglucosyl, bis-deglucosyl, and aglycone derivatives, respectively). Fluorescence recovery after photobleaching (FRAP) measurements on cholesterol-containing planar lipid bilayers revealed that avenacin A-1 caused a small but significant reduction in the lateral diffusion of the phospholipid probe N-(7-nitrobenzoyl-2-oxa-1,3-diazol-4-yl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE). Similarly, with the sterol probe (22-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3beta-ol (NBD-Chol), avenacin A-1, but not its derivatives, caused a more pronounced reduction in the lateral diffusion than that observed with the phospholipid probe. The data indicate that an intact sugar moiety of avenacin A-1 is required to reorganize membrane cholesterol into pores. |
| The metabolic fate of apolipoprotein A-I-containing lipoproteins internalized into HepG2 cells: resecreted lipoproteins as a potent inducer for cholesterol efflux Sasahara, T., S. Kobori, et al. (1994), Atherosclerosis 106(2): 179-90. Abstract: In a chase study using double-radiolabeled apolipoprotein (apo) A-I-containing lipoproteins (14C-labeled cholesteryl ester and 125I-labeled apolipoprotein) with or without apo A-II (Lp A-I/A-II particle and Lp A-I particle), these lipoproteins internalized into HepG2 cells were demonstrated to be time-dependently released into the medium as trichloroacetic acid (TCA)-precipitable fraction. The molar ratio of 14C/125I-radioactivity of TCA-precipitable fraction in the medium was time-dependently decreased. In Sephacryl S-300 HR chromatography of both circulating mature and resecreted apo A-I-containing lipoproteins in the medium after the chase period, a single major protein peak corresponding to that of high density lipoproteins was detected by absorbance at 280 nm. The 14C-radioactivity in apo A-I-containing lipoproteins resecreted from HepG2 cells after 3-h chase was approximately one-fourth of that in circulating mature apo A-I-containing lipoproteins. Cholesterol mass in resecreted apo A-I-containing lipoproteins was three-tenths of that in circulating mature apo A-I-containing lipoproteins. In a cholesterol efflux experiment using macrophage foam cells labeled with 3Hcholesterol, apo A-I-containing lipoproteins resecreted significantly decreased cholesteryl ester radioactivity in macrophage foam cells, as compared with circulating mature apo A-I-containing lipoproteins. There were no remarkable differences in the metabolic fates and cholesterol efflux from macrophage foam cells between Lp A-I and Lp A-I/A-II particles. These results suggest that a part of apo A-I-containing lipoproteins internalized into HepG2 cells may be resecreted in the form of intact lipoproteins with lower cholesterol content, and apo A-I-containing lipoproteins resecreted may be a potent inducer for cholesterol efflux through the processes of reverse cholesterol transport. |
| The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease Ledmyr, H., A. D. McMahon, et al. (2004), Circulation 109(19): 2279-84. Abstract: BACKGROUND: The microsomal triglyceride transfer protein (MTP) transfers lipids into apolipoprotein B-containing lipoproteins for secretion from liver, intestine, and heart. The T-variant of a functional polymorphism in the MTP promoter, MTP-493G/T, has been associated with reduced low-density lipoprotein cholesterol concentrations. We hypothesize that this polymorphism impacts on coronary heart disease (CHD) risk. METHODS AND RESULTS: The effect of the polymorphism was therefore tested in the West of Scotland Coronary Prevention Study biobank (580 cases and 1160 controls). MTP-493T carrier status was associated with significantly increased risk of CHD despite a small reduction in total cholesterol. Compared with the genotypic group with the lowest event rate (MTP-493GG, pravastatin treatment), the respective odds ratios (95% confidence interval) in the placebo group for CHD events were: GG, 1.23 (0.92 to 1.63); GT, 1.53 (1.12 to 2.08); and TT, 2.78 (1.53 to 5.05), suggestive of a gene-dose effect. The excess risk for CHD of the MTP-493T-variant was eliminated by pravastatin treatment. The Uppsala Longitudinal Study of Adult Men (ULSAM), which is a 20-year follow-up study of CHD, was used as an independent confirmatory database. These unexpected findings prompted the investigation of non-plasma lipid factors that could associate the MTP gene with CHD risk. In a limited number of subjects (n=18), heart muscle biopsies showed a MTP-493T genotype-specific depression of MTP mRNA expression. CONCLUSIONS: The MTP-493T variant confers an increased risk of CHD that is unrelated to plasma lipids and lipoproteins, but eliminated by pravastatin treatment. A direct effect of the MTP polymorphism on myocardial lipid metabolism and vulnerability upon ischemic damage cannot be excluded. |
| The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, cytochrome P450scc Black, S. M., J. A. Harikrishna, et al. (1994), Proc Natl Acad Sci U S A 91(15): 7247-51. Abstract: Steroidogenesis is initiated by the conversion of cholesterol to pregnenolone by mitochondrial cytochrome P450scc cholesterol, reduced-adrenal-ferredoxin:oxygen oxidoreductase (side-chain-cleaving); EC 1.14.15.6. Several subsequent steroidal conversions occur in the endoplasmic reticulum (ER), but the last step in the production of glucocorticoids and mineralocorticoids again occurs in the mitochondria. Although cellular compartmentalization of steroidogenic enzymes appears to be a feature of all steroidogenic pathways, some reports indicate that cholesterol can be converted to pregnenolone outside the mitochondria. To investigate whether P450scc can function outside the mitochondria, we constructed vectors producing P450scc and various fusion enzymes of P450scc with electron-transport proteins and directed their expression to either the ER or the mitochondria. Whether targeted to mitochondria or to the ER, plasmid vectors encoding P450scc and fusion proteins of P450scc with either mitochondrial or microsomal electron-transport proteins produced immunodetectable protein. When expressed in mitochondria, all of these constructions converted 22-hydroxycholesterol to pregnenolone, but when expressed in the ER none of them produced pregnenolone. These results show that P450scc can function only in the mitochondria. Furthermore, it appears to be the mitochondrial environment that is required, rather than the specific mitochondrial electron-transport intermediates. |
| The modification of high density lipoproteins by malondialdehyde changes their interaction with J774 macrophages and decreases cholesterol cell efflux Salmon, S., J. C. Maziere, et al. (1990), C R Seances Soc Biol Fil 184(2): 105-13. Abstract: The treatment of HDL3 with malondialdehyde (MDA) results in an increase of the electrophoretic mobility of the particle and in aggregation of the apolipoprotein AI. The binding of MDA-treated-HDL3 to murine macrophages J774 is decreased, as compared to native HDL3. The cholesterol efflux is also markedly reduced. In view of the fact that MDA is produced following plaquette aggregation or oxidative stress, the eventual existence of MDA-modified-HOL in vivo might accelerate the appearance of atherosclerotic lesions by reducing cellular cholesterol efflux. |
| The modulation of thermal properties of vinblastine by cholesterol in membrane bilayers Kyrikou, I., I. Daliani, et al. (2004), Biochim Biophys Acta 1661(1): 1-8. Abstract: It has been shown that the partitioning of vinblastine in 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) single and multiple bilayer dispersions induces partial interdigitation of the lipid alkyl chains. Similar behavior has been observed for abietic and ursodeoxycholic acids and may well be generalized for the partitioning of bulky amphoteric molecules, which tend to localize in the vicinity of the polar heads. For the present study, differential scanning calorimetry (DSC) has been employed to investigate the role of lipid molecular characteristics such as the alkyl chain length and the polarity of the head-group, as well as the impact of cholesterol upon vinblastine-induced interdigitation. It is found that vinblastine does not induce interdigitation in lipids with either shorter or longer alkyl chains than DPPC, or having head-groups of different polarity. In addition, it is shown that the presence of cholesterol in the lipid bilayer tends to modulate the phase behavior of the lipid/vinblastine bilayer system. Preliminary studies show that such properties directly affect the encapsulation efficiency and the pharmacokinetics of liposomes. |
| The molecular and metabolic basis of biliary cholesterol secretion and gallstone disease Zanlungo, S. and F. Nervi (2003), Front Biosci 8: s1166-74. Abstract: This article presents an up to date of selected aspects of the molecular mechanisms of cholesterol metabolism most likely involved in cholesterol gallstones disease, a highly prevalent disease in the Western world. The etiology of cholesterol cholelithiasis is considered to be multifactorial, with interaction of genetic and environmental factors. The production of supersaturated bile by the liver of cholesterol is a key early metabolic event underlying cholesterol lithogenesis. Regulation of hepatic cholesterol trafficking within the hepatocyte appears essential for the production of cholesterol supersaturated bile. Impaired sorting of metabolically active hepatic free cholesterol to the bile acid biosynthetic or lipoprotein production pathways leads to an increased availability of cholesterol for preferential channeling of cholesterol to the canalicular membrane and further secretion into bile. Many of these intrahepatic cholesterol trafficking steps are under genetic control and might be influenced by a variety of environmental factors. This review summarizes recent discoveries related to transhepatic cholesterol flux and biliary lipid secretion, which have provided new insights to the regulation of hepatic cholesterol metabolism as related to gallstone disease. |
| The molecular structure of apolipoprotein A-II modulates the capacity of HDL to promote cell cholesterol efflux Bernini, F., L. Calabresi, et al. (1996), Biochim Biophys Acta 1299(1): 103-9. Abstract: The influence of apolipoprotein A-II (apoA-II) molecular structure on the capacity of high density lipoproteins (HDL) to promote cellular cholesterol efflux was investigated in cultured mouse peritoneal macrophages (MPM). Conversion by reduction and carboxamidomethylation of the naturally occurring dimeric apoA-II to its monomeric form in both native or reconstituted HDL did not change apolipoprotein secondary structure and lipoprotein size/composition. All particles containing monomeric apoA-II, i.e., native HDL3 or reconstituted HDL with or without apoA-I, showed a higher ability to promote cholesterol efflux originating from plasma membrane and intracellular stores, compared to particles containing dimeric apoA-II. These findings indicate that apolipoprotein molecular structure is a major determinant of HDL capacity to promote cholesterol efflux from cells. |
| The morphology and composition of cholesterol, protein, and bilirubin deposits in dried human bile: cathodoluminescence and backscattered electron imaging Loginov, A. S., S. M. Chebanov, et al. (1998), Scanning 20(6): 442-6. Abstract: This work is the first to deal with the application of color cathodoluminescence scanning electron microscopy (CCL SEM) and a novel version of combined imaging with backscattered electrons (CCL + BSE SEM) for the study of the composition of bile and its precipitation mechanisms. The present study demonstrates cholesterol, protein, and bilirubin distribution in deposits of normal and abnormal human bile after solution evaporation to full dryness. Qualitative CCL SEM analysis showed that dried bile remnants include different proportions of the above components. Three types of deposits were observed: Arborescent crystals, typical cholesterol crystals, and amorphous bilirubin particles. The selection of crystalline or amorphous precipitate phases is determined by the dehydration/concentration process. The findings may explain key features in lithogenesis. |
| The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor gamma ligands Chen, Y., S. R. Green, et al. (2005), Biochem Biophys Res Commun 332(1): 188-93. Abstract: We have previously shown that the expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1, is induced by plasma cholesterol. The present study examines the mechanisms that regulate monocyte CCR2 expression in hypercholesterolemia using a mouse model. Our data demonstrate that in the mouse, CCR2 expression in circulating monocytes is controlled by two promoters P1 and P2. The two distinct transcripts, which encode the same protein, are produced by alternative splicing in the 5'-untranslated region. Both promoters are constitutively active, but only P2 is stimulated by cholesterol. However, both promoters are repressed by peroxisome proliferator-activated receptor gamma. |
| The multidrug transporter, P-glycoprotein, actively mediates cholesterol redistribution in the cell membrane Garrigues, A., A. E. Escargueil, et al. (2002), Proc Natl Acad Sci U S A 99(16): 10347-52. Abstract: P-glycoprotein (P-gp) is a plasma membrane ATP-binding cassette transporter, responsible for multidrug resistance in tumor cells. P-gp catalyzes the ATP hydrolysis-dependent efflux of numerous amphiphilic compounds of unrelated chemical structures. In the absence of any identified substrate, P-gp exhibits an apparently futile, basal ATPase activity. By using native membrane vesicles containing high amounts of P-gp, we show here that (i) this basal ATPase activity is tightly dependent on the presence of cholesterol in the membrane; (ii) the stimulation of P-gp ATPase activity by drugs transported by P-gp is higher in the absence than in the presence of cholesterol and, conversely, the stimulation of P-gp ATPase activity by cholesterol is higher in the absence than in the presence of known P-gp substrates; (iii) P-gp mediates the ATP-dependent relocation of cholesterol from the cytosolic leaflet to the exoplasmic leaflet of the plasma membrane; and (iv) the decrease of the cholesterol dependence of P-gp ATPase activity induced by known P-gp substrates is correlated with the inhibition of the ATP-dependent cholesterol redistribution within the membrane. These data are highly evocative of a coupling between the basal ATPase activity of P-gp and its intramembrane cholesterol-redistribution function, and they are fully consistent with the possibility that P-gp may actively translocate cholesterol in the membrane. Finally, this P-gp-mediated cholesterol redistribution in the cell membrane makes it likely that P-gp contributes in stabilizing the cholesterol-rich microdomains, rafts and caveolae, and that it is involved in the regulation of cholesterol trafficking in cells. |
| The Munster Heart Study (PROCAM): total mortality in middle-aged men is increased at low total and LDL cholesterol concentrations in smokers but not in nonsmokers Cullen, P., H. Schulte, et al. (1997), Circulation 96(7): 2128-36. Abstract: BACKGROUND: Some large epidemiological studies have shown an increase in mortality at low levels of total and LDL cholesterol. It has been speculated that low cholesterol levels may play a causative role in this association. To investigate this question, we analyzed all deaths occurring among middle-aged men in the Munster Heart Study (PROCAM), one of the largest prospective epidemiological studies of coronary heart disease risk markers in Europe. METHODS AND RESULTS: In the Munster Heart Study, 10,856 men aged 36 to 65 years at study entry (46.8+/-7.3 years mean+/-SD) were followed for 4 to 14 years (7.1+/-2.4 years). During this period, 313 deaths occurred--46 from myocardial infarction, 48 from suspected or definite sudden cardiac death, 14 from cerebrovascular disease, and 10 from other diseases of the circulatory system. There were 121 deaths from cancer and 33 deaths from violent causes (injuries in 16, suicide in 14, and homicide in 3 cases). Death in 29 cases occurred from other causes and was unexplained in 12 cases. Total cholesterol, LDL cholesterol, and the LDL/HDL ratio showed a J-shaped relationship with total mortality. At high total and LDL cholesterol concentrations, increased mortality was due to increased coronary deaths. At low total and LDL cholesterol concentrations, increased mortality was seen in smokers only and was explained by an increase in smoking-related cancer deaths. CONCLUSIONS: The increase in mortality at low levels of total and LDL cholesterol among middle-aged men in the Munster Heart Study is explained by an increase in smoking-related cancer deaths among smokers. |