| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Transitional features in human atherosclerosis. Intimal thickening, cholesterol clefts, and cell loss in human aortic fatty streaks Guyton, J. R. and K. F. Klemp (1993), Am J Pathol 143(5): 1444-57. Abstract: The possible transition from a subset of fatty streaks to fibrous plaques in human atherosclerosis has long been postulated, but transitional features in lesions have rarely been demonstrated. We examined human aortic fatty streaks to determine whether significant tendencies toward intimal thickening and toward deep extracellular lipid deposition might be found. To provide accurate ultrastructural assessment of lipid, tissues were processed by new electron microscopic cytochemical techniques. Unilateral fatty streaks exhibited a 60% increase in intimal thickness when compared to contralateral control tissue. Fat droplets in intimal cells accounted for approximately half of the increase; nonfat portions of cells and extracellular matrix accounted for the remainder. Six of 32 fatty streaks (19%) contained cholesterol clefts, which were found in the musculo-elastic (deep) layer of the intima or in the tunica media. Volume fractions occupied by cells in deep intima were reduced when cholesterol clefts were evident, suggesting loss of cells in early core regions. Light and electron microscopy showed structures consistent with lipid-rich core regions in lesions with cholesterol clefts and in a few lesions without cholesterol clefts. The findings of intimal thickening, core region formation, and disappearance of intimal cells constitute new evidence that some fatty streaks are progressive lesions and sites of eventual fibrous plaque development. The findings also suggest that the lipid-rich core region does not originate primarily from the debris of dead foam cells in the superficial intima, but instead arises from lipids accumulating gradually in the extracellular matrix of the deep intima. |
| Translational regulation of hepatic HMG-CoA reductase by dietary cholesterol Chambers, C. M. and G. C. Ness (1997), Biochem Biophys Res Commun 232(2): 278-81. Abstract: The question of whether dietary cholesterol exerts feedback regulation on hepatic HMG-CoA reductase at the level of translation was examined by performing polysome profile analysis. Liver polysomes from rats fed 2% cholesterol in their diets for 3 days were compared with those isolated from rats fed a normal chow diet. Northern blotting analysis of the individual fractions revealed that cholesterol feeding reduced the portion of HMG-CoA reductase mRNA associated with translationally active polysomes by over 50% and progressively increased the percentage of reductase mRNA present in the monosomal fractions. In the lightest monosomal fraction over 10 times as much reductase mRNA was present in samples from cholesterol animals as compared to controls. These findings indicate that dietary cholesterol exerts significant feedback regulation on hepatic HMG-CoA reductase at the translational level. |
| Translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the endoplasmic reticulum for esterification may require common cellular factors involved in cholesterol egress from the acidic compartments (lysosomes/endosomes) Spillane, D. M., J. W. Reagan, Jr., et al. (1995), Biochim Biophys Acta 1254(3): 283-94. Abstract: Using a stable cell line 25-RA derived from wild-type Chinese hamster ovary (CHO) cells as the parental cell, this laboratory previously reported the isolation and characterization of CHO cell mutants (cholesterol-trafficking or CT) defective in transporting LDL-derived cholesterol out of the acidic compartment(s) (lysosomes/endosomes) to the endoplasmic reticulum (ER) for esterification. In this report, we show that the CT mutation can be complemented by fusion with human cells; however, attempts to complement the CT defect through DNA transfection have resulted in a collection of stable cell lines designated as ST cells. Under cholesterol starvation condition, the ST cells exhibit an elevated rate of cholesterol ester biosynthesis (by 3- to 5-fold) compared to both the parental CHO cells and the CT cells. The phenotypes of the ST cells are stable. ST cells are thus new cell lines arisen from the CT cells. When the plasma membranes of the parental, CT, and ST cells are labelled with 3Hcholesterol, ST cells show rates of 3Hcholesterol esterification much higher than that observed in CT cells but lower than that observed in the parental CHO cells. This result shows that translocation of plasma membrane cholesterol to the ER for esterification is defective in the CT cells. This result also suggests that ST cells acquire increased cholesterol trafficking activity between the lysosome and the ER without mixing the plasma membrane cholesterol pool. The characteristics of CT cells and ST cells reported here suggest that translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the ER for esterification may require common cellular factors involved in cholesterol egress from the acidic compartment(s) (lysosomes/endosomes). |
| Transmembrane orientation of hydrophobic alpha-helices is regulated both by the relationship of helix length to bilayer thickness and by the cholesterol concentration Ren, J., S. Lew, et al. (1997), Biochemistry 36(33): 10213-20. Abstract: A fluorescence-based approach to evaluate the regulation of transmembrane orientation of alpha-helices has been developed to examine the behavior of a membrane-inserted alpha-helical peptide with a 19 residue hydrophobic sequence. The emission lambdamax of a Trp residue in the helix was used to determine its location in the bilayer. To calibrate this method, Trp lambdamax and depth (determined by parallax analysis of fluorescence quenching) were measured for transmembrane peptides with Trp at different positions. Transmembrane orientation of the alpha-helix was found to be destabilized by differences between the width of the bilayer and the length of the hydrophobic sequence (i.e., hydrophobic mismatch). When bilayer width exceeded the length of the hydrophobic segment, mismatch induced formation of a nontransmembraneous orientation close to the polar/hydrocarbon interface. By manipulation of bilayer width in situ, it was found that the transmembrane and nontransmembrane orientations could interconvert. Cholesterol altered the transmembrane/nontransmembrane equilibrium to a degree consistent with its tendency to increase bilayer thickness. Evaluation of the energetics of transmembrane vs nontransmembrane insertion showed increased mismatch of a helix with bilayer width by the equivalent of just one hydrophobic residue can destabilize transmembrane orientation by roughly 0.5 kcal/mol. Inclusion of 30 mol % cholesterol in a bilayer can alter transmembrane insertion stability by 3-5 kcal/mol. Thus, physiologically relevant variations in both the hydrophobic helix length/membrane thickness ratio and the cholesterol levels influence transmembrane insertion significantly. |
| Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure-function relationships and studies in a compound heterozygous proband Argyropoulos, G., A. Jenkins, et al. (1998), J Lipid Res 39(9): 1870-6. Abstract: Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency. Exon sequence determination of the LCAT gene of the proband revealed two novel heterozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino acid substitutions (Thr13Met and Pro307Ser, respectively). To assess the distinct functional impact of the separate mutant alleles, studies were conducted in the proband's 3-generation pedigree. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband's mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. The proband's father and two daughters were heterozygous for the Thr13Met mutation and also displayed low HDL, reduced LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely impaired in the compound heterozygous proband and was reduced by 50% in individuals heterozygous for either mutation, compared to wild type family members. It is also shown that the two mutations impair both catalytic activity and expression of the circulating protein. |
| Transport of cholesterol across a BeWo cell monolayer: implications for net transport of sterol from maternal to fetal circulation Schmid, K. E., W. S. Davidson, et al. (2003), J Lipid Res 44(10): 1909-18. Abstract: The placental transport of various compounds, such as glucose and fatty acids, has been well studied. However, the transport of cholesterol, a sterol essential for proper fetal development, remains undefined in the placenta. Therefore, the purpose of these studies was to examine the transport of cholesterol across a placental monolayer and its uptake by various cholesterol acceptors. BeWo cells, which originated from a human choriocarcinoma, were grown on transwells for 3 days to form a confluent monolayer. The apical side of the cells was radiolabeled with either free cholesterol or LDL cholesteryl ester. After 24 h, the radiolabel was removed and cholesterol acceptors were added to the basolateral chamber. Cholesterol was found to be taken up by the apical surface of the placental monolayer, transported to the basolateral surface of the cell, and effluxed to fetal human serum, fetal HDL, or phospholipid vesicles, but not to apolipoprotein A-I. In addition, increasing the cellular cholesterol concentration further increased the amount of cholesterol transported to the basolateral acceptors. These are the first studies to demonstrate the movement of cholesterol across a placental cell from the maternal circulation (apical side) to the fetal circulation (basolateral side). |
| Transport of cholesterol by high density lipoproteins from the standpoint of protein biochemistry Titov, V. N. (1995), Vopr Med Khim 41(3): 2-8. |
| Transport of cholesterol from the endoplasmic reticulum to the plasma membrane is constitutive in CaCo-2 cells and differs from the transport of plasma membrane cholesterol to the endoplasmic reticulum Field, F. J., E. Born, et al. (1998), J Lipid Res 39(2): 333-43. Abstract: The transport of newly synthesized cholesterol from its site of synthesis, the endoplasmic reticulum, to the plasma membrane was studied in CaCo-2 cells. The appearance of newly synthesized cholesterol on the cell surface was rapid. By 30 min, 50% of the total labeled cholesterol was observed in the plasma membrane. The arrival of cholesterol at the plasma membrane was independent of new protein synthesis, a functional Golgi apparatus, or microtubular function. Progesterone, verapamil, and trifluoperazine, inhibitors of p-glycoprotein which are known to inhibit cholesterol transport from the plasma membrane to the endoplasmic reticulum, reduced the amount of newly synthesized cholesterol reaching the plasma membrane. The p-glycoprotein inhibitors, however, caused the accumulation of sterol intermediates in the plasma membrane, suggesting that sterol trafficking to the plasma membrane remained intact, but that trafficking from the plasma membrane to the endoplasmic reticulum was disrupted. In contrast, nigericin, another potent inhibitor of cholesterol movement from the plasma membrane to the endoplasmic reticulum, did not alter the transport of newly synthesized cholesterol to the plasma membrane. Moreover, promoting cholesterol transport from the plasma membrane to the endoplasmic reticulum by sphingomyelin hydrolysis or by micellar cholesterol influx did not alter the percent of newly synthesized cholesterol transported to the plasma membrane. Likewise, preventing plasma membrane cholesterol from reaching the endoplasmic reticulum by incubating cells with lysophosphatidylcholine, filipin, or digitonin did not alter the arrival of newly synthesized cholesterol to the plasma membrane. The results suggest that the amount of cholesterol moving to the plasma membrane from the endoplasmic reticulum is constitutive and regulated at the level of cholesterol synthesis and not at the level of the transport process. The pathways of cholesterol transport to and from the plasma membrane are distinct. |
| Transport of cholesterol into mitochondria is rate-limiting for bile acid synthesis via the alternative pathway in primary rat hepatocytes Pandak, W. M., S. Ren, et al. (2002), J Biol Chem 277(50): 48158-64. Abstract: Bile acid synthesis occurs mainly via two pathways: the "classic" pathway, initiated by microsomal cholesterol 7alpha-hydroxylase (CYP7A1), and an "alternative" (acidic) pathway, initiated by sterol 27-hydroxylase (CYP27). CYP27 is located in the inner mitochondrial membrane, where cholesterol content is very low. We hypothesized that cholesterol transport into mitochondria may be rate-limiting for bile acid synthesis via the "alternative" pathway. Overexpression of the gene encoding steroidogenic acute regulatory (StAR) protein, a known mitochondrial cholesterol transport protein, led to a 5-fold increase in bile acid synthesis. An increase in StAR protein coincided with an increase in bile acid synthesis. CYP27 overexpression increased bile acid synthesis by <2-fold. The rates of bile acid synthesis following a combination of StAR plus CYP27 overexpression were similar to those obtained with StAR alone. TLC analysis of (14)C-labeled bile acids synthesized in cells overexpressing StAR showed a 5-fold increase in muricholic acid; in chloroform-extractable products, a dramatic increase was seen in bile acid biosynthesis intermediates (27- and 7,27-hydroxycholesterol). High-performance liquid chromatography analysis showed that 27-hydroxycholesterol accumulated in the mitochondria of StAR-overexpressing cells only. These findings suggest that cholesterol delivery to the inner mitochondrial membrane is the predominant rate-determining step for bile acid synthesis via the alternative pathway. |
| Transport of HDL cholesterol esters to the liver is not diminished by probucol treatment in rats Richard, B. M., M. A. Pfeuffer, et al. (1992), Arterioscler Thromb 12(7): 862-9. Abstract: This study examined the relation of decreased high density lipoprotein (HDL) levels in probucol-fed rats and the transport of HDL cholesterol esters (CEs) to the liver. HDLs from both control rats and rats fed 1% probucol for 3 weeks were doubly labeled in their CE and apolipoprotein A-I moieties with intracellularly trapped tracers and then intravenously injected into probucol-fed or control rats for determination of plasma decay kinetics and sites of tracer uptake. Results for HDL from control and probucol-fed rats were not different. The fractional catabolic rate (FCR) of plasma HDL CE was significantly increased by probucol feeding (23%) so that mass transport of HDL CE through the plasma compartment was not significantly different from that in control rats. The plasma FCR for apolipoprotein A-I did not change. Similarly, the FCR for uptake of HDL CE by the liver increased on probucol feeding (20%), resulting in a near-normal rate of HDL CE mass uptake, whereas the FCR for HDL particle uptake (measured by apolipoprotein A-I uptake) did not change. Thus, the maintenance of near-normal HDL CE uptake by the liver was exclusively due to increased selective uptake (32%). To the extent that hepatic uptake of HDL CE mediates reverse cholesterol transport, that process was not significantly compromised in rats fed 1% probucol. |
| Transport of monovalent cations into erythrocytes of rabbits with experimental hypercholesterolemia: correlation with plasma cholesterol Makarov, V. L., S. R. Kuznetsov, et al. (1994), Biokhimiia 59(7): 1011-9. Abstract: The activities of the Na+, K(+)-pump, Na+, K+, 2Cl- and K+, Cl(-)-cotransports and Na+, Li+ exchange as well as intracellular concentrations of Na+, K+, Mg2+ and cholesterol content in erythrocyte membranes of rabbits with experimental hypercholesterolemia have been studied. The activity of the Na+, K(+)-pump recorded as the ouabain-inhibited component of 86Rb influx is, on the average, by 100% higher than that in control erythrocytes of rabbits fed on a cholesterol-rich diet for 2 months and correlates significantly with the concentration of cholesterol (Ch) and low density lipoproteins (LDL) in the plasma as well as with Na+ concentration in erythrocytes. The activity of the Na+, K+, 2Cl- and K+, Cl(-)-cotransports recorded, correspondingly, as the bumetanide- and furosemide-inhibited component of 86Rb influx, is unobserved in rabbit erythrocytes irrespective of the Ch level in the plasma. The activity of the Na+, Li+ exchange is markedly reduced in erythrocytes of rabbits with hypercholesterolemia and correlates with Ch and LDL levels in the plasma. The K+ and Mg2+ concentrations in erythrocytes do not depend on Ch plasma levels. There was a negative correlation between the intracellular Na+ content with plasma Ch and LDL levels. The Ch content in erythrocyte ghosts is, on the average, identical for both groups of experimental animals. |
| Transport of plasma membrane-derived cholesterol and the function of Niemann-Pick C1 Protein Wiegand, V., T. Y. Chang, et al. (2003), Faseb J 17(6): 782-4. Abstract: To visualize the intracellular transport of plasma membrane-derived cholesterol under physiological and pathophysiological conditions, a novel fluorescent cholesterol analog, 6-dansyl cholestanol (DChol), has been synthesized. We present several lines of evidence that DChol mimics cholesterol. The cholesterol probe could be efficiently incorporated into the plasma membrane via cyclodextrin-donor complexes. The itinerary of DChol from the plasma membrane to the cell was studied to determine its dependence on the function of Niemann-Pick C1 (NPC) protein. In all cells, DChol moved from the plasma membrane to the endoplasmic reticulum. Its further transport to the Golgi complex was observed but with marked differences among various cell lines. DChol was finally transported to small (approximately 0.5 microm diameter) lipid droplets, a process that required functional acyl-CoA:cholesterol acyltransferase. In human NPC fibroblasts, NPC-like cells, or in cells mimicking the NPC phenotype, DChol was found in enlarged (>1 microm diameter) droplets. When the NPC-phenotype was corrected by transfection with NPC1, DChol was again found in small-sized droplets. Our data show that NPC1 has an essential role in the distribution of plasma membrane-derived cholesterol by maintaining the small size of cholesterol-containing lipid droplets in the cell. |
| Transsphenoid endoscopic management of petrous apex cholesterol granuloma Griffith, A. J. and J. E. Terrell (1996), Otolaryngol Head Neck Surg 114(1): 91-4. |
| Trapping crystal nucleation of cholesterol monohydrate: relevance to pathological crystallization Solomonov, I., M. J. Weygand, et al. (2005), Biophys J 88(3): 1809-17. Abstract: Crystalline nucleation of cholesterol at the air-water interface has been studied via grazing incidence x-ray diffraction using synchrotron radiation. The various stages of cholesterol molecular assembly from monolayer to three bilayers incorporating interleaving hydrogen-bonded water layers in a monoclinic cholesterol.H(2)O phase, has been monitored and their structures characterized to near atomic resolution. Crystallographic evidence is presented that this multilayer phase is similar to that of a reported metastable cholesterol phase of undetermined structure obtained from bile before transformation to the triclinic phase of cholesterol.H(2)O, the thermodynamically stable macroscopic form. According to grazing incidence x-ray diffraction measurements and crystallographic data, a transformation from the monoclinic film structure to a multilayer of the stable monohydrate phase involves, at least initially, an intralayer cholesterol rearrangement in a single-crystal-to-single-crystal transition. The preferred nucleation of the monoclinic phase of cholesterol.H(2)O followed by transformation to the stable monohydrate phase may be associated with an energetically more stable cholesterol bilayer arrangement of the former and a more favorable hydrogen-bonding arrangement of the latter. The relevance of this nucleation process of cholesterol monohydrate to pathological crystallization of cholesterol from cell biomembranes is discussed. |
| Treating average cholesterol levels in patients with coronary heart disease Lindbloom, E. J. (1999), J Fam Pract 48(2): 94-5. |
| Treating high cholesterol: everyday applications of the national guidelines Olin, J. W. and M. D. Cressman (1991), Cleve Clin J Med 58(2): 114-5. |
| Treating isolated low high-density lipoprotein cholesterol: prescient or premature? Harper, C. R. and T. A. Jacobson (2000), Am J Cardiol 85(4): 484-6. |
| Treating low HDL-cholesterol in normocholesterolaemic patients with coronary disease: statins, fibrates or horses for courses? Watts, G. F. (2004), Eur Heart J 25(9): 716-9. |
| Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin Brown, A. S., R. G. Bakker-Arkema, et al. (1998), J Am Coll Cardiol 32(3): 665-72. Abstract: OBJECTIVES: This study compared the efficacy and safety of atorvastatin, fluvastatin, lovastatin, and simvastatin in patients with documented atherosclerosis treated to U.S. National Cholesterol Education Program (NCEP) recommended low-density-lipoprotein (LDL) cholesterol concentration (< or = 100 mg/dl 2.59 mmol/liter). BACKGROUND: For patients with advanced atherosclerosis, NCEP recommends lipid-lowering drug therapy if LDL cholesterol remains > or = 130 mg/dl (3.36 mmol/liter). METHODS: A total of 318 men or women with documented atherosclerosis and LDL cholesterol > or = 130 mg/dl (3.36 mmol/liter) and < or = 250 mg/dl (6.5 mmol/liter), and triglycerides < or = 400 mg/dl (4.5 mmol/liter) participated in this 54-week, multicenter, open-label, randomized, parallel-group, active-controlled, treat-to-target study. Patients were titrated at 12-week intervals until the LDL cholesterol goal was reached. Number of patients reaching target LDL cholesterol levels and dose to reach target were evaluated. RESULTS: At the starting doses, atorvastatin 10 mg produced significantly greater decreases (p < 0.05) in plasma LDL cholesterol than the other treatments. Subsequently, the percentage of patients reaching goal at the starting dose was 32% for atorvastatin, 1% for fluvastatin, 10% for lovastatin and 22% for simvastatin. Atorvastatin-treated patients required a lower median dose than other treatments. Median doses at week 54 with the last available visit carried forward were atorvastatin 20 mg/day, fluvastatin 40 mg/day + colestipol 20 g/day, lovastatin 80 mg/day, simvastatin 40 mg/day. CONCLUSIONS: A significantly greater number (p < 0.05) of patients with confirmed atherosclerosis treated with atorvastatin reached the target LDL cholesterol concentration at the starting dose than patients treated with fluvastatin or lovastatin, and significantly fewer (p < 0.05) patients treated with atorvastatin required combination therapy with colestipol to achieve target LDL cholesterol concentrations than all other statins tested. |
| Treating to meet NCEP-recommended LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease Hunninghake, D., R. G. Bakker-Arkema, et al. (1998), J Fam Pract 47(5): 349-56. Abstract: BACKGROUND: Our study compared use of atorvastatin, fluvastatin, lovastatin, and simvastatin for lowering low-density lipoprotein (LDL) cholesterol concentration in patients at risk for coronary heart disease (CHD). The goal was to reach the LDL cholesterol levels recommended by the National Cholesterol Education Program (NCEP). METHODS: A combined total of 344 men and women took part in this 54-week, multicenter, open-label, randomized, parallel-group, active-controlled, treat-to-target study. Patients were selected on the basis of their LDL cholesterol concentration and their risk for CHD. During treatment, doses were titrated at 12-week intervals to a maximum of 80 mg per day of atorvastatin and lovastatin, or 40 mg per day of fluvastatin and simvastatin, with colestipol added if necessary to attain the NCEP-recommended LDL cholesterol concentration. RESULTS: At the starting dose, atorvastatin decreased plasma LDL cholesterol significantly (P <.05) compared with the other reductase inhibitors, and the percentage of patients reaching target LDL cholesterol concentration at the starting dose was significantly greater in the atorvastatin group (P <.05). Overall, a significantly (P <.05) greater percentage (95%) of atorvastatin-treated patients achieved target LDL cholesterol concentration. The safety profile was similar among all reductase inhibitors tested. CONCLUSIONS: At the starting dose, a significantly (P <.05) greater percentage of atorvastatin-treated patients at risk for CHD reached the target LDL cholesterol concentration than patients with treated with other reductase inhibitors. |