Cholesterol Journal Articles

Record 11101 to 11120

Role of cholesterol in ligand binding and G-protein coupling of serotonin1A receptors solubilized from bovine hippocampus
Chattopadhyay, A., M. Jafurulla, et al. (2005), Biochem Biophys Res Commun 327(4): 1036-41.
Abstract: The serotonin(1A) (5-HT(1A)) receptor is an important member of the superfamily of seven transmembrane domain G-protein-coupled receptors. We report here that solubilization of the hippocampal 5-HT(1A) receptor by the zwitterionic detergent CHAPS is accompanied by loss of membrane cholesterol which results in a reduction in specific agonist binding activity and extent of G-protein coupling. Importantly, replenishment of cholesterol to solubilized membranes using MbetaCD-cholesterol complex restores the cholesterol content of the membrane and significantly enhances the specific agonist binding activity and G-protein coupling. These novel results provide useful information on the role of cholesterol in solubilization of G-protein-coupled receptors, an important step for molecular characterization of these receptors.

Role of cholesterol in lipid raft formation: lessons from lipid model systems
Silvius, J. R. (2003), Biochim Biophys Acta 1610(2): 174-83.
Abstract: Biochemical and cell-biological experiments have identified cholesterol as an important component of lipid 'rafts' and related structures (e.g., caveolae) in mammalian cell membranes, and membrane cholesterol levels as a key factor in determining raft stability and organization. Studies using cholesterol-containing bilayers as model systems have provided important insights into the roles that cholesterol plays in determining lipid raft behavior. This review will discuss recent progress in understanding two aspects of lipid-cholesterol interactions that are particularly relevant to understanding the formation and properties of lipid rafts. First, we will consider evidence that cholesterol interacts differentially with different membrane lipids, associating particularly strongly with saturated, high-melting phospho- and sphingolipids and particularly weakly with highly unsaturated lipid species. Second, we will review recent progress in reconstituting and directly observing segregated raft-like (liquid-ordered) domains in model membranes that mimic the lipid compositions of natural membranes incorporating raft domains.

Role of cholesterol in regulating apolipoprotein B secretion by the liver
Thompson, G. R., R. P. Naoumova, et al. (1996), J Lipid Res 37(3): 439-47.
Abstract: The review examines the evidence that the supply of cholesterol available for incorporation into nascent lipoprotein particles exerts a regulatory influence on apolipoprotein (apo) B secretion by the liver. Support for this hypothesis comes both from in vitro experiments and from recent observations in normal subjects and patients with dyslipidemia associated with familial hypercholesterolemia, obesity, noninsulin dependent diabetes mellitus, growth hormone deficiency and cholesteryl ester storage disease. The findings do not negate a role for triglyceride synthesis in determining apoB secretion in very low density lipoprotein, but the inhibitory effects on the latter process of pharmacological blockade of cholesterol synthesis or esterification suggest that it is conditional upon an adequate supply of cholesteryl ester.

Role of cholesterol in sperm capacitation
Cross, N. L. (1998), Biol Reprod 59(1): 7-11.

Role of cholesterol in synapse formation and function
Pfrieger, F. W. (2003), Biochim Biophys Acta 1610(2): 271-80.
Abstract: Cholesterol is a multifaceted molecule, which serves as essential membrane component, as cofactor for signaling molecules and as precursor for steroid hormones. Consequently, defects in cholesterol metabolism cause devastating diseases. So far, the role of cholesterol in the nervous system is less well understood. Recent studies showed that cultured neurons from the mammalian central nervous system (CNS) require glia-derived cholesterol to form numerous and efficient synapses. This suggests that the availability of cholesterol in neurons limits the extent of synaptogenesis. Here, I will summarize the experimental evidence for this hypothesis, describe what is known about the structural and functional role of cholesterol at synapses, and discuss how cholesterol may influence synapse development and stability.

Role of cholesterol in the formation and nature of lipid rafts in planar and spherical model membranes
Crane, J. M. and L. K. Tamm (2004), Biophys J 86(5): 2965-79.
Abstract: Sterols play a crucial regulatory and structural role in the lateral organization of eukaryotic cell membranes. Cholesterol has been connected to the possible formation of ordered lipid domains (rafts) in mammalian cell membranes. Lipid rafts are composed of lipids in the liquid-ordered (l(o)) phase and are surrounded with lipids in the liquid-disordered (l(d)) phase. Cholesterol and sphingomyelin are thought to be the principal components of lipid rafts in cell and model membranes. We have used fluorescence microscopy and fluorescence recovery after photobleaching in planar supported lipid bilayers composed of porcine brain phosphatidylcholine (bPC), porcine brain sphingomyelin (bSM), and cholesterol to map the composition-dependence of l(d)/l(o) phase coexistence. Cholesterol decreases the fluidity of bPC bilayers, but disrupts the highly ordered gel phase of bSM, leading to a more fluid membrane. When mixed with bPC/bSM (1:1) or bPC/bSM (2:1), cholesterol induces the formation of l(o) phase domains. The fraction of the membrane in the l(o) phase was found to be directly proportional to the cholesterol concentration in both phospholipid mixtures, which implies that a significant fraction of bPC cosegregates into l(o) phase domains. Images reveal a percolation threshold, i.e., the point where rafts become connected and fluid domains disconnected, when 45-50% of the total membrane is converted to the l(o) phase. This happens between 20 and 25 mol % cholesterol in 1:1 bPC/bSM bilayers and between 25 and 30 mol % cholesterol in 2:1 bPC/bSM bilayers at room temperature, and at approximately 35 mol % cholesterol in 1:1 bPC/bSM bilayers at 37 degrees C. Area fractions of l(o) phase lipids obtained in multilamellar liposomes by a fluorescence resonance energy transfer method confirm and support the results obtained in planar lipid bilayers.

Role of cholesterol in the microsomal membrane
Brenner, R. R. (1990), Lipids 25(10): 581-5.

Role of cholesterol in the modulation of interdigitation in phosphatidylethanols
Bondar, O. P. and E. S. Rowe (1998), Biochim Biophys Acta 1370(2): 207-17.
Abstract: Phosphatidylethanol (Peth) is formed in biological membranes when ethanol replaces water in the transphosphatidylation reaction catalyzed by phospholipase D. This charged lipid accumulates in the presence of ethanol, and it has unusual properties that can influence membrane structure and function. We have previously shown that dimyristoylphosphatidylethanol (DMPeth) and dipalmitoylphosphatidylethanol (DPPeth) form the interdigitated gel phase in the presence of Tris-HCl O.P. Bondar, E.S. Rowe, Biophys. J., 71 (1996) 1440-1449. In the present investigation, differential scanning calorimetry (DSC) and fluorescence have been used to investigate the effect of cholesterol on the phase behavior of DPPeth and DMPeth. Our results show that cholesterol prevents the formation of the interdigitated phase in the presence of Tris-HCl, and that ethanol counters this influence and restores the ability of these lipids to interdigitate. Pyrene-PC fluorescence probe was used in this investigation and gave results that were in agreement with the conclusions based on the DSC study.

Role of cholesterol in the regulation of growth plate chondrogenesis and longitudinal bone growth
Wu, S. and F. De Luca (2004), J Biol Chem 279(6): 4642-7.
Abstract: Inborn errors of cholesterol synthesis are associated with multiple systemic abnormalities, including skeletal malformations. The regulatory role of cholesterol during embryogenesis appears to be mediated by Shh, a signaling molecule in which activity depends on molecular events involving cholesterol. Based on this evidence, we hypothesized that cholesterol, by modifying the activity of Ihh (another of the Hedgehog family proteins) in the growth plate, regulates longitudinal bone growth. To test this hypothesis, we treated rats with AY 9944, an inhibitor of the final reaction of cholesterol synthesis. After 3 weeks, AY 9944 reduced the cumulative growth, tibial growth, and the tibial growth plate height of the rats. To determine whether cholesterol deficiency affects bone growth directly at the growth plate, we then cultured fetal rat metatarsal bones in the presence of AY 9944. After 4 days, AY 9944 suppressed metatarsal growth and growth plate chondrocyte proliferation and hypertrophy. The inhibitory effect on chondrocyte hypertrophy was confirmed by the AY 9944-mediated decreased expression of collagen X. Lastly, AY 9944 decreased the expression of Ihh in the metatarsal growth plate. We conclude that reduced cholesterol synthesis in the growth plate, possibly by altering the normal activity of Ihh, results in suppressed longitudinal bone growth and growth plate chondrogenesis.

Role of cholesterol in the regulation of renal phosphate transport
Wang, H., H. Zajicek, et al. (1997), Front Biosci 2: d43-8.
Abstract: The kidney plays a critical role in the regulation of inorganic phosphate (Pi) homeostasis through changes in the proximal tubular apical membrane Na-dependent Pi (Na/Pi) transport activity. In response to alterations in dietary Pi intake and during the aging process, changes in renal Na/Pi transport activity are inversely correlated with apical membrane cholesterol content. Cholesterol regulates Na/Pi transport activity by fluidity-dependent and fluidity-independent mechanisms, including regulation of Na/Pi protein transcription, synthesis, and trafficking to and from the plasma membrane.

Role of cholesterol in the structural order of lens membrane lipids
Borchman, D., R. J. Cenedella, et al. (1996), Exp Eye Res 62(2): 191-7.
Abstract: Cholesterol may order or disorder phospholipids. The physiological contribution of cholesterol to the structural order of lens membrane lipids was determined. Cholesterol and phospholipid from bovine lens nuclear and cortical tissue were separated by thin layer chromatography. The effect of cholesterol upon the trans to gauche transition of the hydrocarbon chains was assessed by measuring CH2 infrared stretching band frequencies as cholesterol was added back to the phospholipids. Although the relative cholesterol level of nuclear lipid was much higher than that of the cortex (59 vs. 36 mol%, respectively), the structural order of unfractionated nuclear and cortical lipids were similar at physiological temperature. Cholesterol added to lipids devoid of cholesterol produced a sharp biphasic effect on the structural order of nuclear lipids, increasing the trans conformation from 56% to 0 mol% cholesterol to 74% at 18% cholesterol to 41% trans at 59 mol% cholesterol. Cholesterol addition produced a shallow biphasic change in the percentage trans conformation of cortical lipids. Maximum order (about 40% trans conformation) was seen at a cholesterol level equal to that of intact cortical lipid (36 mol%). The physiological role of cholesterol is to increase the structural order of cortical membrane lipid and decrease order in nuclear lipid. The net result is a similarity in the structural order of cortical and nuclear membrane. We suggest that the different response of cortical and nuclear lipids to added cholesterol is linked to differences in the phospholipid composition between these two lens regions. In the absence of cholesterol, nuclear phospholipids are much more highly ordered than those of the cortex.

Role of cholesterol synthesis and esterification in the growth of CEM and MOLT4 lymphoblastic cells
Dessi, S., B. Batetta, et al. (1997), Biochem J 321 (Pt 3): 603-8.
Abstract: CEM and MOLT4 are human T-cell lines isolated from patients with acute cell leukaemia. In culture they show important differences in cholesterol metabolism, CEM being less efficient at synthesizing cholesterol and having a lower activity of 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase. To investigate further the relationship between regulation of intracellular cholesterol metabolism at various steps and rate of cell growth, cholesterol synthesis, esterification and efflux were evaluated in CEM and MOLT4 cells at different times during exponential and stationary growth in vitro. It was shown that, although CEM cells have a lower rate of cholesterol synthesis, they grow at a faster rate than MOLT4 cells. However, CEM cells exhibit an increased capacity to esterify cholesterol associated with a decreased efflux of newly synthesized cholesterol into the medium. These results provide evidence for an association between the capability to synthesize and retain cell cholesterol esters and the growth rate potential.

Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans
Mitchell, J. C., B. G. Stone, et al. (1991), J Lipid Res 32(7): 1143-9.
Abstract: We used lovastatin, a specific inhibitor of HMG-CoA reductase, to study the role of cholesterol synthesis in regulation of both bile acid synthesis, measured by release of 14CO2 from 26-14Ccholesterol, and biliary cholesterol secretion, measured by standard marked perfusion techniques, in humans. Six volunteers were studied in each of four periods: a) control; b) 6-10 hours after a single 40 mg oral dose of lovastatin to study acute effects; c) after 5-6 weeks of lovastatin 40 mg orally twice a day to study steady-state effects; and d) 24 h after cessation of chronic lovastatin. Mean bile acid synthesis fell to 69% of control (P less than 0.01) after single-dose lovastatin and remained at 83% of control after 5-6 weeks on lovastatin (P less than 0.05). After withdrawal of lovastatin, mean bile acid synthesis was 88% of control (NS). Mean biliary cholesterol secretion did not change after single-dose lovastatin (103% of control), but fell to 81% of control during chronic lovastatin treatment (P less than 0.05). After withdrawal of lovastatin, mean cholesterol secretion remained at 80% of control (P less than 0.05). These data suggest that in humans cholesterol synthesis is an immediate regulator of bile acid synthesis. Cholesterol synthesis also regulates biliary cholesterol secretion, but the effect is not immediate and therefore may be indirect.

Role of cholesterol, calcium, and mitochondrial activity in the susceptibility for cryodamage after a cycle of freezing and thawing
Meseguer, M., N. Garrido, et al. (2004), Fertil Steril 81(3): 588-94.
Abstract: OBJECTIVE: To correlate the levels of two concrete sperm markers, cholesterol and Ca(+2), together with mitochondrial activity on raw semen samples with the post-thaw recovery of spermatozoa with progressive motility on human sperm samples as the first step to improve sperm cryostorage protocols. DESIGN: Controlled prospective research project. SETTING: Private and university-affiliated setting. PATIENT(S): Semen samples from 122 males attending our center for infertility (n = 47) or semen donation (n = 75) were studied. INTERVENTION(S): The mean basic semen parameters of the 122 semen samples studied before and after the freezing and thawing process. MAIN OUTCOME MEASURE(S): We determined Ca(+2) and cholesterol concentrations on seminal plasma by enzymoimmunoanalysis techniques, intracellular Ca(+2) concentrations, cholesterol concentrations in the sperm plasma membrane and mitochondrial activity by fluorometry. RESULT(S): Cholesterol concentration in seminal plasma and cholesterol contents in the sperm membrane and mitochondrial activity were studied. No correlations were initially found to be of statistical significance. Regarding seminal plasma and intracellular sperm Ca(+2) concentrations, a statistically significant negative correlation was found (P=.036 and P=.016). CONCLUSION(S): Higher cholesterol contents do not appear to protect sperm against cryodamage. Conversely, Ca(+2) equilibrium appears to be essential for a good post-thaw recovery. Mitochondrial activity is not reflecting the possibilities of sperm survival and is probably not a good indicator of the sperm metabolism.

Role of cholesterol-accumulating macrophages on vascular smooth muscle cell proliferation
Hayashi, K., E. Nishio, et al. (1992), Clin Biochem 25(5): 345-9.
Abstract: The proliferation of vascular smooth muscle cells (VSMC) was stimulated by co-incubation with macrophages. Further stimulation was observed when co-incubated macrophages were supplied with LDL or cholesterol. However, the stimulation of VSMC proliferation did not result from co-incubation with macrophages supplemented with acetylated LDL or delipidated LDL. The addition of anti-PDGF antibody partially abolished the stimulation of VSMC proliferation induced by co-incubation with macrophages supplemented with LDL or cholesterol. A high concentration of prostaglandin E2 inhibited the proliferation of VSMC stimulated by PDGF and plasma-derived serum when they were at the G0/G1 stage. However, the inhibitory effect of prostaglandin E2 on proliferation was not observed when cells were incubated with macrophages supplemented with LDL or cholesterol in spite of the promotion under these conditions of prostaglandin E2 production. These results suggest that cholesterol-accumulating macrophages may exert a regulatory effect on the proliferation of VSMC through the synthesis and secretion of platelet-derived growth factor (PDGF) and prostaglandin E2, besides foam-cell formation.

Role of cholesterol-enriched diet and the mevalonate pathway in cardiac nitric oxide synthesis
Giricz, Z., C. Csonka, et al. (2003), Basic Res Cardiol 98(5): 304-10.
Abstract: Cardiac stress adaptation is deteriorated in hyperlipidemia possibly due to deterioration of nitric oxide (NO) metabolism. However, inhibition of HMG-CoA reductase, a key enzyme in the mevalonate pathway, was shown to increase the level of endothelial NO-synthase (eNOS) mRNA. Here we studied the effect of dietary and pharmacologic modulation of the mevalonate pathway on cardiac NO synthesis. Rats were fed 2% cholesterol-enriched or normal diet for 8 weeks. Normal and cholesterol-fed animals were treated with farnesol, a major metabolite of the mevalonate pathway (2.2 mg/kg i.p.) or with the HMG-CoA reductase inhibitor lovastatin (3 x 5 mg/kg per os for 3 days, n = 5-6 in each group). Cardiac NO content was significantly decreased in cholesterol-fed rats as assessed by electron spin resonance spectroscopy, however, other treatments did not influence cardiac NO content. Cardiac activity of Ca(2+)-dependent NOS was unaffected by cholesterol-diet and by treatment with either farnesol or lovastatin, as assessed by (14)C-citrullin assay. Ca(2+)-independent NOS activity was negligible in all groups. Cardiac eNOS protein content measured by Western blotting was also unchanged in all groups. We conclude that cholesterol-diet decreases cardiac NO content, however, cholesterol diet-induced inhibition of the mevalonate pathway does not account for the decreased NO level in the heart, and that the mevalonate pathway does not influence cardiac NO biosynthesis.

Role of cholesteryl ester transfer protein in reverse cholesterol transport
McPherson, R. and Y. Marcel (1991), Clin Cardiol 14(2 Suppl 1): I31-4.
Abstract: Cholesteryl ester transfer protein (CETP) and apolipoprotein E (apo E) play important roles in reverse cholesterol transport in humans. CETP transfers cholesteryl ester (CE) from high-density lipoprotein (HDL) to other lipoproteins, mainly very low-density lipoprotein (VLDL) remnants, which provide a vehicle for the delivery of HDL-derived CE to the liver via apo E or B/E receptors. Using a sensitive and specific radioimmunoassay, we have demonstrated that plasma concentrations of CETP vary dependent on gender, the concentration and composition of plasma lipoproteins, and dietary cholesterol intake. Plasma CETP appears to increase as an adaptive response to increased peripheral flux of cholesterol. Probucol therapy results in a significant increase in plasma CETP concentration, which may explain, in part, the marked effect of this agent on HDL concentration and composition.

Role of common genetic polymorphisms in the LDL receptor gene in affecting plasma cholesterol levels in the general population
Ahn, Y. I., M. I. Kamboh, et al. (1994), Arterioscler Thromb 14(5): 663-70.
Abstract: A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the autosomal dominant disorder familial hypercholesterolemia. In addition, a number of common DNA polymorphisms have been identified in the LDL receptor gene, but their significance in affecting plasma cholesterol levels in the general population has not been studied widely. We investigated the role of two common DNA polymorphisms, Ava II (exon 13) and Nco I (exon 18), at the LDL receptor locus in affecting plasma lipid profiles in normolipidemic Hispanics (n = 385) and non-Hispanic whites (NHWs; n = 543) from the San Luis Valley, Colorado. While the distribution of the Nco I polymorphism was comparable between Hispanics and NHWs, the allele frequencies at the Ava II restriction site differed significantly between the two ethnic groups (P <.001). The Ava II and Nco I polymorphisms were in linkage disequilibrium (P <.05) in both Hispanics and NHWs. Both polymorphisms revealed a gender-specific effect on total and LDL cholesterol (LDL-C) confined to women only in both ethnic groups. The AVA II polymorphism was associated significantly with total cholesterol and LDL-C in NHW women (P =.001 and P =.014) and in Hispanic women (P =.011 and P =.057). The effect of the Nco I polymorphism was significant on total cholesterol and LDL-C (P =.019 and P =.035) in Hispanic women only. Although a similar trend was observed in NHW women, the effect was not significant at the 5% level.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of CYP27A in cholesterol and bile acid metabolism
Dubrac, S., S. R. Lear, et al. (2005), J Lipid Res 46(1): 76-85.
Abstract: The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.

Role of dietary cholesterol in the optimal diet for the treatment of hypercholesterolemia
Illingworth, D. R., L. F. Hatcher, et al. (1995), Can J Cardiol 11 Suppl G: 115G-117G.
Abstract: OBJECTIVE: This paper discusses studies in which the effects of dietary cholesterol on the plasma concentrations of lipids and lipoproteins have been evaluated in adult human subjects including patients with hypo- and hypercholesterolemia. DESIGN: The dietary studies were conducted on an outpatient basis in the Clinical Research Center. Each dietary period was four weeks in duration and an adequate washout period was interposed between each dietary phase. SETTING: A university medical centre. PATIENTS: The participants in these studies were adult men or women with hypocholesterolemia, normal volunteers or patients with primary hypercholesterolemia. INTERVENTIONS: The dietary periods consisted of three separate dietary phases in which dietary cholesterol was a single variable. The diets contained 50 mg/day of cholesterol for the low cholesterol diet, 350 mg/day for the moderate cholesterol diet and 650 mg/day for the high cholesterol diet. RESULTS: Concentrations of total and low density lipoprotein (LDL) cholesterol increased in all three patient groups from the low cholesterol to the moderate cholesterol to the high cholesterol diet but the magnitude of increase in LDL cholesterol concentrations was greater in the patients with pre-existent hypercholesterolemia and least in the patients with hypocholesterolemia. In all three patients groups an increased intake of dietary cholesterol was associated with suppression of endogenous cholesterol biosynthesis as assessed by the urinary excretion of mevalonic acid. CONCLUSIONS: An increased intake of dietary cholesterol results in increases in the plasma concentrations of total and LDL cholesterol in patients with inherently low, normal or high concentrations of LDL cholesterol but the magnitude of increase is greatest in those patients with pre-existent hypercholesterolemia. These results support the view that restriction of dietary cholesterol leads to a reduction in the plasma concentrations of total and LDL cholesterol and is an appropriate recommendation for patients with known hypercholesterolemia or patients in whom medical recommendations call for a reduction in the plasma concentrations of total and LDL cholesterol.

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Cholesterol Journal Articles