| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Carotid atherosclerosis in men with low levels of HDL cholesterol Wilt, T. J., H. B. Rubins, et al. (1997), Stroke 28(10): 1919-25. Abstract: BACKGROUND AND PURPOSE: A low HDL cholesterol (HDL-C) frequently occurs in conjunction with a desirable LDL cholesterol (LDL-C) and is a risk factor for coronary heart disease (CHD). Additionally, the presence of carotid atherosclerosis is a strong and independent predictor of morbidity and mortality in patients with CHD. This article describes the prevalence and correlates of sonographically detected carotid atherosclerosis in men with low levels of HDL-C and CHD but without elevated levels of LDL-C or total cholesterol. METHODS: High-resolution B-mode ultrasonography was used to quantify intima-media wall thickness (IMT) in the common and internal carotid arteries and at the carotid artery bifurcation in 202 randomly selected male veterans with CHD and low levels of HDL-C who are participating in the VA HDL Intervention Trial. Ultrasonographic measurement of carotid artery wall stiffness was determined in a subset of 94 of these individuals. RESULTS: The mean maximum and single greatest carotid artery IMT measurements were 1.41 and 2.58 mm, respectively. The prevalence of ultrasound-detected carotid atherosclerosis as defined by a mean maximum IMT > or = 1.3 mm was 58.9% and by single maximum IMT > or = 1.5 mm was 87.1%. IMT was associated with increased age, lower extremity arterial disease, systolic blood pressure, and ultrasonographically measured carotid artery stiffness. CONCLUSIONS: Men with low levels of HDL-C and CHD but without elevated LDL-C or total cholesterol have a very high prevalence of ultrasound-detected carotid artery atherosclerosis. |
| Case 1: a patient with elevated low-density lipoprotein cholesterol Friedewald, V. E., Jr. and A. M. Gotto, Jr. (2000), Am J Cardiol 85(1): 131. |
| Case 2: a patient with low levels of high-density lipoprotein cholesterol Friedewald, V. E., Jr. and A. M. Gotto, Jr. (2000), Am J Cardiol 85(3): 403, A10. Abstract: Approximately 11% of all American men >20 years of age have low levels of high-density lipoprotein cholesterol (<35 mg/dl) in isolation, with an even higher prevalence in high-risk populations. One feature of the 1993 National Cholesterol Education Program guidelines-and the focus of this month's CME-accredited case study-is an increased emphasis on high-density lipoprotein cholesterol levels as an important aspect of risk stratification for coronary heart disease. |
| Case number 26: massive cholesterol crystal deposition: unusual location in rheumatoid arthritis Balint, P. V., D. Kane, et al. (2003), Ann Rheum Dis 62(6): 512. |
| Case report: failure of adrenal scintigraphy to exhibit 131I cholesterol uptake in a CT-demonstrated, surgically proven aldosteronoma Salam, Z., H. Lubbos, et al. (1996), Am J Med Sci 312(3): 130-2. Abstract: This is the case of a large 2 x 1.5 cm adrenal tumor demonstrated on CT scan that was proven biochemically and surgically to be an aldosteronoma and that did not concentrate 6-beta(131I)-iodo-methyl-19-norcholesterol (NP-59). Before the publication of this case, all CT-identified aldosteronomas of greater than 1 cm have concentrated NP-59. Previously, an adrenal mass of greater than 1 cm that failed to concentrate NP-59 was excluded from being an aldosteronoma. This concept must be reevaluated with the publication of this case. |
| Catabolites of cholesterol synthesis pathways and forskolin as activators of the farnesoid X-activated nuclear receptor Howard, W. R., J. A. Pospisil, et al. (2000), Toxicol Appl Pharmacol 163(2): 195-202. Abstract: The nuclear receptors are a family of transcriptional mediators that, upon activation, bind DNA and regulate gene transcription. Among these receptors, the farnesoid X-activated receptor (FXR) has recently been identified as one activated by bile acids and farnesol. To investigate the potential of other sterols to activate FXR, as well as to examine relevant relationships among identified activators of FXR, the current study used a mammalian cell transcription assay to quantify and compare activation potential. In addition to the classical bile acids deoxycholate (DCA) and chenodeoxycholate (CDCA), FXR was shown to be transcriptionally active in the presence of the androgen catabolites 5alpha-androstan-3alpha-ol-17-one (androsterone) and 5beta-androstan-3alpha-ol-17-one (etiocholanolone), as well as the sterol bronchodilatory drug forskolin. Conversely, cholesterol and several other key precursors to the androgens and bile acids were either not active or only slightly active. Furthermore, it was observed that the bile acid ursodeoxycholate (UDCA) could inhibit DCA and CDCA activation of FXR in a manner parallel to its ability to antagonize DCA and CDCA induction of apoptosis. By far, the most efficacious activator of FXR was forskolin. Interestingly, although it is classically viewed as an initiator of the adenylate cyclase/protein kinase A (PKA) pathway, PKA inhibition did not inhibit forskolin's activation of FXR nor was cyclic AMP (cAMP) able to stimulate FXR-mediated transcription. These data would suggest that forskolin acts as a ligand for FXR rather than as a secondary activator of FXR and could have important implications with respect to its potential toxicity and pharmacological use. |
| Catalytically inactive lecithin: cholesterol acyltransferase (LCAT) caused by a Gly 30 to Ser mutation in a family with LCAT deficiency Yang, X. P., A. Inazu, et al. (1997), J Lipid Res 38(3): 585-91. Abstract: Plasma lecithin:cholesterol acyltransferase (LCAT) plays an important role in early steps of reverse cholesterol transport, i.e., cholesterol efflux from peripheral tissues and cholesterol esterification in HDL. However, structural and functional relationships of LCAT have not been fully elucidated. We described a missense mutation of Gly 30-to-Ser in a patient with classical LCAT deficiency. The proband was homozygous for the mutation and had a very low level of HDL cholesterol (2 mg/dl), with a half of normal LCAT mass (2.75 micrograms/ml), but no detectable or very low LCAT activity in endogenous and exogenous substrate assays. Both his mother and sister were heterozygous for the mutation, and had slightly decreased levels of HDL cholesterol (34 and 36 mg/dl, respectively). Transient expression study using COS cells indicated that mutant cDNA produces similar amounts of media protein as compared to wild type, but no detectable LCAT activity. The missense mutation may result in a near-native conformation without large effects on cellular secretion but a catalytically defective protein. Thus, the N-terminal domain appears crucial for enzymatic activity, in addition to the catalytically active consensus sequence of Gly179 to Gly183 and a putative sterol binding domain of Glu154 to Lys173. |
| Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells Lindstedt, L., M. Lee, et al. (2003), Biochem Biophys Res Commun 312(4): 1019-24. Abstract: In atherosclerosis, accumulation of cholesterol in macrophages may partially depend on its defective removal by high-density lipoproteins (HDL). We studied the proteolytic effect of cathepsins F, S, and K on HDL(3) and on lipid-free apoA-I, and its consequence on their function as inductors of cholesterol efflux from cholesterol-filled mouse peritoneal macrophages in vitro. Incubation of HDL(3) with cathepsin F or S, but not with cathepsin K, led to rapid loss of prebeta-HDL, and reduced cholesterol efflux by 50% in only 1min. Cathepsins F or K partially degraded lipid-free apoA-I and reduced its ability to induce cholesterol efflux, whereas cathepsin S totally degraded apoA-I, leading to complete loss of apoA-I cholesterol acceptor function. These results suggest that cathepsin-secreting cells induce rapid depletion of lipid-poor (prebeta-HDL) and lipid-free apoA-I and inhibit cellular cholesterol efflux, so tending to promote the formation and maintenance of foam cells in atherosclerotic lesions. |
| Cationic cholesterol promotes gene transfection using the nuclear localization signal in protamine Noguchi, A., N. Hirashima, et al. (2002), Pharm Res 19(7): 933-8. Abstract: PURPOSE: The purpose of this study was to evaluate protamine-mediated gene transfection by liposomes with a novel cationic cholesterol derivative (I) compared to those with DC-Chol or DOTMA (Lipofectin). METHOD: Plasmid pGL3 DNA was complexed to the cationic liposomes with the derivative (I), DC-Chol, or DOTMA in SFM101(Nissui) at room temperature for 15 min, and thereafter the complex was incubated with target cells (NIH3T3) for 4 h at 37 degrees C. The cells then were washed and cultured for another 40 h in the growth medium at 37 degrees C before luciferase assay. RESULTS: The transfection efficiency by the liposomes with the derivative (I) was much higher than that by the liposomes with DC-Chol or DOTMA. In addition, its transfection efficiency was enhanced greatly by the addition of protamine. Atomic force microscopy showed clearly how the size of the DNA-liposome complex was changed by protamine. Furthermore, fluorescence microscopic images showed that Cy5-labeled antisense DNAs were transferred quicker into the nucleus of the target cells by the liposomes with the derivative I in the presence of protamine. CONCLUSION: Although there exist several possible mechanisms, such as improved protection of DNA intracellularly by derivative (I), one possibility is that the DNA-protamine-liposome complex with the derivative (I) promoted gene transfection more significantly into the nucleus of the target cells using the nuclear localization signal of protamine. |
| Cationic cholesterol with a hydroxyethylamino head group promotes significantly liposome-mediated gene transfection Okayama, R., M. Noji, et al. (1997), FEBS Lett 408(2): 232-4. Abstract: A novel cationic cholesterol derivative with a hydroxyethylamino head group, cholesteryl-3beta-carboxyamidoethylene-N-hydroxyethylamine (II), has been synthesized and used for liposome-mediated gene transfection. The cationic liposomes containing the derivative (II) facilitated greatly pSV2CAT gene transfection into mouse NIH3T3 and L929 cells in the absence of serum. The transfection efficiency was much higher than those by the cationic liposomes containing cationic derivatives with a dialkylamino head group (I, III or IV). Further, the efficiency by the cationic liposomes with the derivative (II) was not so much decreased in the presence of serum. This suggested that a novel cationic cholesterol derivative (II) should be very promising in liposome-mediated gene transfection of plasmid and antisense DNA into target cells. |
| Cationic lipids (lipofectamine) and disturbance of cellular cholesterol and sphingomyelin distribution modulates gamma-secretase activity within amyloid precursor protein in vitro Urmoneit, B., J. Turner, et al. (1998), Prostaglandins Other Lipid Mediat 55(5-6): 331-43. Abstract: To study beta-amyloid protein generation we expressed different amyloid precursor protein (APP) isoforms in the human neuroblastoma cell line SY5Y (for details see (1)). Treatment with lipofectamine, an cationic lipid for eucaryotic cell transfection, inhibits gamma-secretase activity and stimulates the physiological APP cleavage by alpha-secretase activity. Beside the MDL inhibitor (2), this is the second agent that shows modulation of gamma-secretase activity in vitro. Further, we show that disturbance of cellular cholesterol and sphingomyelin distribution in transfected SY5Y cells results in an overproduction of beta-amyloid protein. This provides experimental evidence that membrane instability influenced the proteolytic activity of gamma-secretase within the APP molecule. |
| Cation-induced aggregation of acidic phospholipid vesicles: the role of fatty acid unsaturation and cholesterol Eklund, K. K., J. E. Takkunen, et al. (1991), Chem Phys Lipids 57(1): 59-66. Abstract: Cation-induced aggregation of acidic phospholipid vesicles consisting of dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylserine (DPPS), phosphatidylserine from bovine brain (brPS), and phosphatidylglycerol from egg yolk (eggPG) was studied. Significant differences were evident in the NaCl-induced aggregation of fully saturated and unsaturated acidic phospholipid vesicles. The threshold NaCl concentration of vesicle aggregation (NaClThr) for DPPS vesicles was 320 mM compared to 610 mM observed for brPS vesicles. For DMPG vesicles the NaClThr was 430 mM and no aggregation of eggPG vesicles could be observed upon addition of NaCl. The threshold CaCl2 concentrations of aggregation of DMPG and eggPG vesicles were 2.3 and 4.9 mM, respectively. The corresponding threshold CaCl2 concentrations for DPPS and brPS vesicles were 0.85 mM and 1.3 mM, respectively. The inclusion of cholesterol into vesicles attenuated NaCl- and CaCl2-induced aggregation of DMPG and DPPS vesicles. However, enhancement of aggregation by inclusion of cholesterol was observed in the case of NaCl-induced aggregation of brPS vesicles. It is concluded that cation mediated membrane-membrane interactions depend, in addition to polar headgroup structure, on the fatty acid composition of the phospholipids also. |
| Causal link between low cholesterol and cancer is unlikely Sonnichsen, A. C., C. Otto, et al. (1995), Bmj 311(7017): 1438. |
| Causal relationship between occlusive lesions of the coronary artery and myocardial fibrosis in arteriosclerotic rabbits--differences between cholesterol-fed and heritable hyperlipidemic rabbits Nakamura, M., S. Abe, et al. (1996), Atherosclerosis 124(1): 37-47. Abstract: To investigate the causal relationship between lesions of either the proximal large or the distal small coronary arteries and myocardial fibrosis, the hearts and the aortas of 99 cholesterol-fed rabbits with either intermittent or continuous hyperlipidemia for 8 months or more, 44 Watanabe-heritable hyperlipidemic (WHHL) rabbits and 20 normal rabbits were studied histologically. The size and location of the myocardial fibrosis correlated closely with the almost completely occlusive distal small coronary artery which mainly consisted of macrophages, necrosis and calcification but did not correlate with the maximum % stenosis of the large proximal subepicardial coronary arteries in the cholesterol-fed-rabbits. Myocardial fibrosis and almost completely occlusive lesions of the distal small coronary arteries were very rare in the WHHL rabbits, and the maximum % stenosis of the proximal coronary artery and aortic lesions in the WHHL rabbits tended to be greater than those in the cholesterol-fed rabbits. Thus, we are still not certain as to whether or not, the organic stenosis of the subepicardial coronary artery is responsible for myocardial fibrosis in WHHL-rabbits. In conclusion, a causal relationship was observed between myocardial fibrosis and the occlusive lesions of the distal small coronary arteries in cholesterol-fed rabbits, while the arteriosclerotic lesions of the small coronary artery in cholesterol-fed rabbits completely differed from those observed in WHHL-rabbit. |
| Causes of high blood cholesterol Grundy, S. M. and G. L. Vega (1990), Circulation 81(2): 412-27. |
| Caveolae and cholesterol distribution in vascular smooth muscle cells of different phenotypes Thyberg, J. (2002), J Histochem Cytochem 50(2): 185-95. Abstract: Vascular smooth muscle cells (SMCs) grown in primary culture are converted from a contractile to a synthetic phenotype. This includes a marked morphological reorganization, with loss of myofilaments and formation of a large ER-Golgi complex. In addition, the number of cell surface caveolae is distinctly reduced and the handling of lipoprotein-derived cholesterol changed. Here we used filipin as a marker to study the distribution of cholesterol in SMCs by electron microscopy. In contractile cells, filipin-sterol complexes were preferentially found in caveolae and adjacent ER cisternae (present in both leaflets of the membranes). After exposure to LDL or cholesterol, labeling with filipin was increased both in membrane organelles and in the cytoplasm. In contrast, treatment with mevinolin (a cholesterol synthesis inhibitor) or beta-cyclodextrin (a molecule that extracts cholesterol from cells) decreased the reaction with filipin but did not affect the close relation between the ER and the cell surface. In synthetic cells, filipin-sterol complexes were diffusely spread in the plasma membrane and the strongest cytoplasmic reaction was noted in endosomes/lysosomes, both under normal conditions and after incubation with LDL or cholesterol. On the basis of the present findings, we propose a mechanism for direct exchange of cholesterol between the plasma membrane and the ER and more active in contractile than in synthetic SMCs. |
| Caveolae and intracellular trafficking of cholesterol Fielding, C. J. and P. E. Fielding (2001), Adv Drug Deliv Rev 49(3): 251-64. Abstract: Caveolae, free cholesterol (FC)-rich microdomains of the plasma membrane, are both a terminus for the intracellular transit of newly synthesized and recycling cellular FC, and a site for FC efflux to the extracellular medium. The same domains play key roles as locations for the assembly of signaling complexes and for the endocytosis of selected ligands. Caveolin, the major structural protein of caveolae, plays a regulatory role in growth, the cell cycle, and cell adhesion. Each of these functions is FC-dependent. Caveolae appear to act as both sensors and regulators of cellular FC content, and in this way mediate an array of membrane-dependent cell functions. |
| Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains Harder, T. and K. Simons (1997), Curr Opin Cell Biol 9(4): 534-42. Abstract: There is accumulating evidence that lateral assemblies (rafts) of sphingolipids and cholesterol form platforms that serve to support numerous cellular events in membrane traffic and signal transduction. Raft membrane microdomains are thought to function by preferentially associating with specific proteins while excluding others. The basic forces driving raft formation are lipid interactions which are, per se, weak and transient. Sphingolipid rafts should therefore be considered to be dynamic structures in which cholesterol plays an important role as a linker. Caveolins influence these dynamics by forming stabilized raft domains in intracellular membranes as well as at the plasma membrane. Recent data suggest that clustering of raft components could regulate raft dynamics and therefore represents an important feature in the function of these membrane microdomains. |
| Caveolin is present in intestinal cells: role in cholesterol trafficking? Field, F. J., E. Born, et al. (1998), J Lipid Res 39(10): 1938-50. Abstract: It was postulated that specialized microdomains of the plasma membrane, consistent with caveolae, might play a role in cholesterol trafficking in intestinal cells. The existence, therefore, of caveolin and the role of detergent-resistant microdomains of the plasma membrane in cholesterol trafficking were investigated in human small intestine and CaCo-2 cells. Caveolin mRNA was detected by RT-PCR in small intestinal brushings and biopsies and in CaCo-2 cells. Northern hybridization of caveolin mRNA detected 3 kb and 0.8 kb transcripts in CaCo-2 cells. From brushings of distal duodenum and in CaCo-2 cells, Western analysis for detection of caveolin protein demonstrated a 21 kDa-sized protein and a 600 kDa homooligomer. In CaCo-2 cells, caveolin was demonstrated by immunofluorescence in apical membranes as well as within cells. Using sucrose-density gradients, caveolin was localized to detergent-resistant microdomains of the plasma membrane. As determined by cholesterol oxidase-accessible cholesterol, 3-5% of plasma membrane cholesterol in CaCo-2 cells was estimated to be in these detergent-resistant microdomains. After the absorption of cholesterol from bile-salt micelles, more plasma membrane cholesterol moved to these specialized microdomains within the plasma membrane and was esterified. In CaCo-2 cells, filipin, N-ethyl maleimide, and cholesterol depletion, treatments that disrupt caveolar function, interfered with the transport of plasma membrane cholesterol to the endoplasmic reticulum, whereas okadaic acid, sphingomyelinase, and cholesterol oxidase did not. Changes in cholesterol flux at the apical membrane of the cell did not alter mRNA levels or mass of caveolin. The results suggest that caveolin is present in intestinal and CaCo-2 cells and is associated with detergent-resistant microdomains of cellular membranes. With the influx of micellar cholesterol from the lumen, plasma membrane cholesterol moves or "clusters" to these microdomains and is transported to the endoplasmic reticulum for esterification and eventual transport. Caveolin/caveolae may play a role in cholesterol trafficking in intestinal cells. |
| Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation Smart, E. J., Y. S. Ying, et al. (1994), J Cell Biol 127(5): 1185-97. Abstract: Caveolae are a membrane specialization used to internalize molecules by potocytosis. Caveolin, an integral membrane protein, is associated with the striated coat present on the cytoplasmic surface of the caveolae membrane. We now report that oxidation of caveolar cholesterol with cholesterol oxidase rapidly displaces the caveolin from the plasma membrane to intracellular vesicles that colocalize with Golgi apparatus markers. After the enzyme is removed from the medium, caveolin returns to caveolae. When untreated cells are gently homogenized, caveolin on the plasma membrane is accessible to both anti-caveolin IgG and trypsin. After cholesterol oxidase treatment, however, Golgi-associated caveolin is inaccessible to both of these molecules. Brefeldin A, which inhibits ER to Golgi trafficking, blocks the appearance of caveolin in the Golgi apparatus but does not prevent caveolin from leaving the plasma membrane. Indirect immunogold localization experiments show that in the presence of cholesterol oxidase caveolin leaves the plasma membrane and becomes associated with endoplasmic reticulum and Golgi compartments. Surprisingly, the loss of caveolin from the plasma membrane does not affect the number or morphology of the caveolae. |