| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The extracorporeal elimination of LDL cholesterol von Baeyer, H. and R. Schwerdtfeger (1991), Dtsch Med Wochenschr 116(39): 1494. |
| The extracorporeal elimination of LDL cholesterol by apheresis. The indications and methods Olbricht, C. J. (1991), Dtsch Med Wochenschr 116(16): 625-30. |
| The family of thiol-activated, cholesterol-binding cytolysins Palmer, M. (2001), Toxicon 39(11): 1681-9. Abstract: Several species of both pathogenic and non-pathogenic grampositive bacteria within the genera Streptococcus, Clostridium and Bacillus secrete cytolytic proteins that belong to a single, highly homologous family. The most widely known members of this family are streptolysin O, listeriolysin, perfringolysin, and pneumolysin. These toxins specifically require membrane cholesterol but, apparently, do not depend on any other specific cell surface receptor, so that they are able to lyse the cytoplasmic membranes of virtually any animal cell. Upon binding as monomers, they oligomerize to form large pores with up to 30 nm internal diameter. These are the largest pores known, permitting permeation not only of ions and small metabolites but also of macromolecules. The latter property renders these toxins useful tools in cell biology.While several of these cytolysins have been shown to be determinants of bacterial pathogenicity, their biological roles may vary, as do the lifestyles of the bacteria secreting them. A unique function is surely fulfilled by listeriolysin O, which helps the intracellular pathogen Listeria monocytogenes escape from phagolysosomes and then spread to adjacent host cells. |
| The farnesoid X-receptor is an essential regulator of cholesterol homeostasis Lambert, G., M. J. Amar, et al. (2003), J Biol Chem 278(4): 2563-70. Abstract: To address the importance of the farnesoid X-receptor (FXR; NR1H4) for normal cholesterol homeostasis, we evaluated the major pathways of cholesterol metabolism in the FXR-deficient (-/-) mouse model. Compared with wild-type, FXR(-/-) mice have increased plasma high density lipoprotein (HDL) cholesterol and a markedly reduced rate of plasma HDL cholesterol ester clearance. Concomitantly, FXR(-/-) mice exhibit reduced expression of hepatic genes involved in reverse cholesterol transport, most notably, that for scavenger receptor BI. FXR(-/-) mice also have increased: (i) plasma non-HDL cholesterol and triglyceride levels, (ii) apolipoprotein B-containing lipoprotein synthesis, and (iii) intestinal cholesterol absorption. Surprisingly, biliary cholesterol elimination was increased in FXR(-/-) mice, despite decreased expression of hepatic genes thought to be involved in this process. These data demonstrate that FXR is a critical regulator of normal cholesterol metabolism and that genetic changes affecting FXR function have the potential to be pro-atherogenic. |
| The fate of cholesterol exiting lysosomes Lange, Y., J. Ye, et al. (1997), J Biol Chem 272(27): 17018-22. Abstract: Cholesterol released from ingested low density lipoproteins in lysosomes moves both to the plasma membrane and to the endoplasmic reticulum (ER) where it is re-esterified. Whether cholesterol can move directly from lysosomes to ER or first must traverse the plasma membrane has not been established. To examine this question, the endocytic pathway of rat hepatoma cells was loaded at 18 degrees C with low density lipoproteins (LDL) labeled with 3Hcholesteryl linoleate, and the label then was chased at 37 degrees C. The hydrolysis of the accumulated ester proceeded linearly for several hours. Almost all of the released 3Hcholesterol moved to the plasma membrane rapidly and without a discernable lag. In contrast, the re-esterification in the ER of the released 3Hcholesterol showed a characteristic lag of 0.5-1 h. These data are inconsistent with direct cholesterol transfer from lysosomes to ER; rather, they suggest movement through the plasma membrane. Furthermore, we found that progesterone, imipramine and 3-beta-2-(diethylamino)ethoxyandrost-5-en-17-one (U18666A) strongly inhibited the re-esterification of lysosomal cholesterol in the ER. However, contrary to previous reports, they did not block transfer of 3Hcholesterol from lysosomes to the cell surface. Therefore, the site of action of these agents was not at the lysosomes. We suggest instead that their known ability to block cholesterol movement from the plasma membrane to the ER accounts for the inhibition of lysosomal cholesterol esterification. These findings are consistent with the hypothesis that cholesterol released from lysosomes passes through the plasma membrane on its way to the ER rather than proceeding there directly. As a result, ingested cholesterol is subject to the same homeostatic regulation as the bulk of cell cholesterol, which is located in the plasma membrane. |
| The fate of lipoprotein cholesterol entering the arterial wall Kruth, H. S. (1997), Curr Opin Lipidol 8(5): 246-52. Abstract: Recent findings have helped to explain the fate of cholesterol entering the arterial wall. LDL can undergo both fusion and aggregation. These changes may cause increased retention of LDL in lesion connective tissue matrix and LDL uptake by macrophages. In the cornea, apparent fusion of LDL occurs in the absence of macrophages. Mast cells may be important in LDL fusion, as mast cell-derived proteases can induce fusion of LDL through proteolysis of apolipoprotein B. LDL in arterial wall atherosclerotic lesions was found to be sialic acid-poor and ceramide-enriched. These chemical changes promote LDL aggregation. Processes that may function to remove cholesterol from the arterial wall have been reported. Macrophage-produced apolipoprotein E can mediate macrophage cholesterol efflux and macrophages can convert cholesterol to 27-oxygenated products that macrophages excrete. Alternately, another oxygenated sterol, 7-ketocholesterol, impairs macrophage cholesterol efflux. In addition, mast-cell derived chymase proteolyses HDL and reduces its capacity to stimulate cholesterol efflux. |
| The fatty acid spectrum and free cholesterol level in exhaled air condensate Rybakova, E. V., V. M. Sidel'nikov, et al. (1991), Lab Delo(4): 74-5. Abstract: Gas chromatographic measurement of fatty acid spectrum and free cholesterol level in exhaled air condensate of children suffering from asthma has revealed a deficiency of polyunsaturated fatty acids and lipids at the expense of linoleic and arachidonic acids. |
| The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities Makowski, L., K. C. Brittingham, et al. (2005), J Biol Chem 280(13): 12888-95. Abstract: Fatty acid-binding proteins are cytosolic fatty acid chaperones, and the adipocyte isoform, aP2, plays an important role in obesity and glucose metabolism. Recently, this protein has been detected in macrophages where it strongly contributes to the development of atherosclerosis. Here, we investigated the role of aP2 in macrophage biology and the molecular mechanisms underlying its actions. We demonstrate that aP2-deficient macrophages display defects in cholesterol accumulation and alterations in pro-inflammatory responsiveness. Deficiency of aP2 alters the lipid composition in macrophages and enhances peroxisome proliferator-activated receptor gamma activity, leading to elevated CD36 expression and enhanced uptake of modified low density lipoprotein. The increased peroxisome proliferator-activated receptor gamma activity in aP2-deficient macrophages is also accompanied by a significant stimulation of the liver X receptor alpha-ATP-binding cassette transporter A1-mediated cholesterol efflux pathway. In parallel, aP2-deficient macrophages display reduced IkappaB kinase and NF-kappaB activity, resulting in suppression of inflammatory function including reduced cyclooxygenase-2 and inducible nitric-oxide synthase expression and impaired production of inflammatory cytokines. Our results demonstrate that aP2 regulates two central molecular pathways to coordinate macrophage cholesterol trafficking and inflammatory activity. |
| The fetoprotein transcription factor (FTF) gene is essential to embryogenesis and cholesterol homeostasis and is regulated by a DR4 element Pare, J. F., D. Malenfant, et al. (2004), J Biol Chem 279(20): 21206-16. Abstract: The fetoprotein transcription factor (FTF) gene was inactivated in the mouse, with a lacZ gene inserted inframe into exon 4. LacZ staining of FTF+/- embryos shows that the mFTF gene is activated at initial stages of zygotic transcription. FTF gene activity is ubiquitous at the morula and blastocyst stages and then follows expression patterns indicative of multiple FTF functions in fetal development. FTF-/- embryos die at E6.5-7.5, with features typical of visceral endoderm dysfunction. Adult FTF+/- mice are hypocholesterolemic, and express liver FTF at about 40% of the normal level. Overexpression of liver FTF in transgenic mice indicates in vivo that FTF is an activator of CYP7A1. However, CYP7A1 expression is increased in FTF+/- liver. Gene expression profiles indicate that higher CYP7A1 expression is caused by attenuated liver cell stress signaling. Diet experiments support a model where FTF is quenched both by activated c-Jun, and by SHP as a stronger feedback mechanism to repress CYP7A1. A DR4 element is conserved in the FTF gene promoter and activated by LXR-RXR and TR-RXR, qualifying the FTF gene as a direct metabolic sensor. Liver FTF increases in rats treated with thyroid hormone or a high cholesterol diet. The FTF DR4 element tightens functional links between FTF and LXRalpha in cholesterol homeostasis and can explain transient surges of FTF gene activities during development and FTF levels lower than predicted in FTF+/- liver. The FTF-lacZ mouse establishes a central role for FTF in developmental, nutritive, and metabolic functions from early embryogenesis through adulthood. |
| The first step of oxygenation in cholesterol biosynthesis Ono, T. (2002), Biochem Biophys Res Commun 292(5): 1283-8. |
| The folly of questioning the benefits of cholesterol reduction Castelli, W. P. (1994), Am Fam Physician 49(3): 567, 570, 572 passim; discussion 57. |
| The formation of large apo e-rich HDL particles in cholesterol-loaded rabbits in vivo Skonner, E. R. and Y. D. Fragoso (1996), Z Gastroenterol 34 Suppl 3: 145-6. |
| The four-legged hepatocyte: lessons learned about cholesterol metabolism from new technologies Raper, S. E. (1996), Hepatology 24(2): 463-5. |
| The Framingham Heart Study shows no increases in coronary heart disease rates from cholesterol values of 205 to 264 mg% Seltzer, C. C. (1991), G Ital Cardiol 21(6): 683. |
| The Friedewald equation for the determination of low-density-lipoprotein cholesterol: a special case Samman, S. and A. S. Truswell (1993), Am J Clin Nutr 58(6): 928-9. |
| The Friedewald formula underestimates LDL cholesterol at low concentrations Scharnagl, H., M. Nauck, et al. (2001), Clin Chem Lab Med 39(5): 426-31. Abstract: Due to recent advances in the treatment of hypercholesterolemia, low density lipoprotein (LDL) cholesterol concentrations below 2.6 mmol/l have become attainable. In general, LDL cholesterol is determined indirectly according to Friedewald. We examined the performance of the Friedewald formula at low concentrations of LDL cholesterol in comparison with a beta-quantification method. We analyzed 176 samples from individuals treated by LDL apheresis with a mean LDL cholesterol concentration of 3.07 mmol/l and found that the Friedewald formula underestimated LDL cholesterol with a bias of -18.5%, -14.5%, -7.3%, and -3.8% at mean LDL cholesterol levels of 1.58, 2.4, 3.49, and 4.67 mmol/l, respectively. Thus, the lower the LDL cholesterol concentration was, the greater the negative bias. We conclude that the Friedewald formula may not be reliable at low LDL cholesterol concentrations produced by LDL apheresis. This finding may also be of relevance to the monitoring of patients being treated with lipid lowering drugs. |
| The functional role of cholesterol: the difference in the pools of cholesterol in the cell and in individual classes of blood lipoproteins (a review of the literature) Titov, V. N. (2000), Klin Lab Diagn(3): 3-10. |
| The functional size of acyl-coenzyme A (CoA):cholesterol acyltransferase and acyl-CoA hydrolase as determined by radiation inactivation Billheimer, J. T., D. A. Cromley, et al. (1990), J Biol Chem 265(15): 8632-5. Abstract: Frozen rat liver microsomes and rough endoplasmic reticulum were irradiated with high energy electrons. The surviving enzymatic activity of acyl-CoA:cholesterol acyltransferase and activity for esterification of 25-hydroxycholesterol decreased as a simple exponential function of radiation exposure, leading to a target size of 170-180 kDa. The loss of acyl-CoA hydrolase activity with a radiation dose was complex and resolved as a 45-kDa enzyme associated with a large inhibitor. It is interpreted that acyl-CoA hydrolase is the acyl-CoA-binding component and the inhibitor is the cholesterol-binding component of acyl-CoA:cholesterol acyltransferase. |
| The future direction of cholesterol-lowering therapy Evans, M., A. Roberts, et al. (2002), Curr Opin Lipidol 13(6): 663-9. Abstract: PURPOSE OF REVIEW: Observational studies suggest a continuous positive relationship between vascular risk and cholesterol without any lower threshold level. We review recent and future clinical trials addressing the question of optimal treatment goals for cholesterol reduction and how these relate to present guidelines. With increasing focus on greater cholesterol reduction, new approaches to lipid-lowering therapy are being developed; we discuss some of these agents including the new statin, rosuvastatin and novel cholesterol transport inhibitors such as ezetimibe. RECENT FINDINGS: The Heart Protection Study demonstrated that LDL cholesterol reduction to levels as low as 1.7 mmol/l was associated with significant clinical benefit in a wide range of high-risk individuals, irrespective of baseline cholesterol levels, with no apparent threshold level for LDL cholesterol with respect to cardiovascular risk. The Heart Protection Study also demonstrated that the benefits of LDL cholesterol reduction extend into peripheral vascular disease and cerebrovascular disease prevention and suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL cholesterol targets of 2.6 mmol/l, may result in undertreatment of a large number of patients. Various large end-point trials, including Treating to New Targets and Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine will attempt to further address the issue of optimal LDL cholesterol reduction. New therapies are being developed to meet the challenge of more intensive cholesterol lowering. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL cholesterol of 40-69% over its dose range of 5-80 mg. Ezetimibe is a selective cholesterol absorption inhibitor, with a site of action at the intestinal epithelium. Optimum reductions in LDL cholesterol of up to 25 and 60% reduction in chylomicron cholesterol content are seen with a 10-mg dose. SUMMARY: Evidence is accumulating supporting the safety and benefits of aggressive cholesterol reduction, with no apparent threshold for LDL cholesterol. New therapies will aid in achieving lower cholesterol levels and the use of combination therapies targeting different aspects of cholesterol metabolism may produce additional benefits. Outcome studies are awaited to further address these issues. |
| The Garden of Eden--plant based diets, the genetic drive to conserve cholesterol and its implications for heart disease in the 21st century Jenkins, D. J., C. W. Kendall, et al. (2003), Comp Biochem Physiol A Mol Integr Physiol 136(1): 141-51. Abstract: It is likely that plant food consumption throughout much of human evolution shaped the dietary requirements of contemporary humans. Diets would have been high in dietary fiber, vegetable protein, plant sterols and associated phytochemicals, and low in saturated and trans-fatty acids and other substrates for cholesterol biosynthesis. To meet the body's needs for cholesterol, we believe genetic differences and polymorphisms were conserved by evolution, which tended to raise serum cholesterol levels. As a result modern man, with a radically different diet and lifestyle, especially in middle age, is now recommended to take medications to lower cholesterol and reduce the risk of cardiovascular disease. Experimental introduction of high intakes of viscous fibers, vegetable proteins and plant sterols in the form of a possible Myocene diet of leafy vegetables, fruit and nuts, lowered serum LDL-cholesterol in healthy volunteers by over 30%, equivalent to first generation statins, the standard cholesterol-lowering medications. Furthermore, supplementation of a modern therapeutic diet in hyperlipidemic subjects with the same components taken as oat, barley and psyllium for viscous fibers, soy and almonds for vegetable proteins and plant sterol-enriched margarine produced similar reductions in LDL-cholesterol as the Myocene-like diet and reduced the majority of subjects' blood lipids concentrations into the normal range. We conclude that reintroduction of plant food components, which would have been present in large quantities in the plant based diets eaten throughout most of human evolution into modern diets can correct the lipid abnormalities associated with contemporary eating patterns and reduce the need for pharmacological interventions. |