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1
Liang, Congxin, Liqun Yan, J�rg-R. Hill, Carl S. Ewig, Terry R. Stouch, and Arnold T. Hagler. "Force field studies of cholesterol and cholesteryl acetate crystals and cholesterol-cholesterol intermolecular interactions." Journal of Computational Chemistry 16, no. 7 (July 1995): 883–97. http://dx.doi.org/10.1002/jcc.540160706.
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Vill, V., J. Thiem, and P. Rollin. "Flüssigkristalline aromatische Cholesterin-Derivate." Zeitschrift für Naturforschung A 47, no. 3 (March 1, 1992): 515–20. http://dx.doi.org/10.1515/zna-1992-0313.
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Abstract Liquid Crystalline Aromatic Cholesterol Derivates A series of aromatic cholesteryl ethers, esters, phenylcarbonates and benzylcarbonates were prepared and their liquid crystalline properties studied. The occurence of ferroelectric phases as well as properties of cholesteric and blue phases alternate with the number of linking atomes between steroid and atomatic system
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Robins, S. J., J. M. Fasulo, C. R. Pritzker, J. M. Ordovas, and G. M. Patton. "Diurnal changes and adaptation by the liver of hamsters to an atherogenic diet." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 269, no. 6 (December 1, 1995): R1327—R1332. http://dx.doi.org/10.1152/ajpregu.1995.269.6.r1327.
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Studies were performed in freely feeding, male (F1B) Syrian hamsters fed a high-fat diet to determine the extent and manner of adaptation of the liver to diurnal changes in eating patterns and an increase in serum lipids. Serum cholesterol and triglycerides strongly paralleled changes in food consumption and were 40-50% greater during the 12-h dark period than the 12-h light period of the diurnal cycle. Hepatic cholesterol changes closely approximated changes in serum cholesterol (r = 0.916) due principally to changes in hepatic cholesteryl esters that were on average about 10-fold greater with the high-fat diet than with a chow diet. With the high-fat diet, hepatic cholesteryl esters were, however, extremely variable and were 40% greater at the mid-dark than at the mid-light period. With high fat there was also a marked increase in the secretion of very low density lipoproteins (VLDL) from the liver that were cholesteryl ester rich and closely paralleled the diurnal changes in hepatic cholesteryl esters (r = 0.911). In contrast, although with a high-fat diet biliary cholesterol secretion was increased, the increase in cholesterol in bile exhibited no diurnal pattern and with the high-fat diet was far less in magnitude than the increase of cholesterol in VLDL. Biliary cholesterol secretion is dependent on bile acid secretion. However, with the high-fat diet, neither the bile acid pool size nor bile acid secretion was increased compared with chow-fed controls. Moreover, with high fat at mid-dark period, bile acid secretion was significantly less than controls at mid-dark period. Thus in these hamsters a high-fat diet produced a marked increase in serum cholesterol that was distinctly diurnal and was compensated for by a diurnal increase in hepatic cholesteryl ester stores and the secretion of cholesteryl esters in VLDL. In contrast, cholesterol secretion in bile did not correspond to the fluctuating changes of cholesterol in the liver and was far less in magnitude than would be necessary to reduce a greatly expanded pool of hepatic cholesterol.
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Rodriguez-Agudo, Daniel, Shunlin Ren, Eric Wong, Dalila Marques, Kaye Redford, Gregorio Gil, Phillip Hylemon, and William M. Pandak. "Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation." Journal of Lipid Research 49, no. 7 (April 9, 2008): 1409–19. http://dx.doi.org/10.1194/jlr.m700537-jlr200.
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Khan, B., H. G. Wilcox, and M. Heimberg. "Cholesterol is required for secretion of very-low-density lipoprotein by rat liver." Biochemical Journal 258, no. 3 (March 15, 1989): 807–16. http://dx.doi.org/10.1042/bj2580807.
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To study potential effects of hepatic cholesterol concentration on secretion of very-low-density lipoprotein (VLDL) by the liver, male rats were fed on unsupplemented chow, chow with lovastatin (0.1%), or chow with lovastatin (0.1%) and cholesterol (0.1%) for 1 week. Livers were isolated from these animals and perfused in vitro, with a medium containing [2-14C]acetate, bovine serum albumin and glucose in Krebs-Henseleit buffer, and with an oleate-albumin complex. With lovastatin feeding, the hepatic concentrations of cholesteryl esters and triacylglycerols before perfusion were decreased, although free cholesterol was unchanged. However, hepatic secretion of all the VLDL lipids was decreased dramatically by treatment with lovastatin. Although total secretion of VLDL triacylglycerol, phospholipid, cholesterol and cholesteryl esters was decreased, the decrease in triacylglycerol was greater than that in free cholesterol or cholesteryl esters, resulting in secretion of a VLDL particle enriched in sterols relative to triacylglycerol. In separate studies, the uptake of VLDL by livers from control animals or animals treated with lovastatin was measured. Uptake of VLDL was estimated by disappearance of VLDL labelled with [1-14C]oleate in the triacylglycerol moiety, and was observed to be similar in both groups. During perfusion, triacylglycerol accumulated to a greater extent in livers from lovastatin-fed rats than in control animals. The depressed output of VLDL triacylglycerols and the increase in triacylglycerol in the livers from lovastatin-treated animals was indicative of a limitation in the rate of VLDL secretion. Addition of cholesterol (either free cholesterol or human low-density lipoprotein) to the medium perfusing livers from lovastatin-fed rats, or addition of cholesterol to the diet of lovastatin-fed rats, increased the hepatic concentration of cholesteryl esters and the output of VLDL lipids. The concentration of cholesteryl esters in the liver was correlated with the secretion of VLDL by the liver. These data suggest that cholesterol is an obligate component of the VLDL required for its secretion. It is additionally suggested that cholesteryl esters are in rapid equilibrium with a small pool of free cholesterol which comprises a putative metabolic pool available and necessary for the formation and secretion of the VLDL. Furthermore, the specific radioactivity (d.p.m./mumol) of the secreted VLDL free cholesterol was much greater than that of hepatic free cholesterol, suggesting that the putative hepatic metabolic pool is only a minor fraction of total hepatic free cholesterol.
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Gylling, H., S. Pyrhönen, E. Mäntylä, H. Mäenpää, L. Kangas, and T. A. Miettinen. "Tamoxifen and toremifene lower serum cholesterol by inhibition of delta 8-cholesterol conversion to lathosterol in women with breast cancer." Journal of Clinical Oncology 13, no. 12 (December 1995): 2900–2905. http://dx.doi.org/10.1200/jco.1995.13.12.2900.
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PURPOSE Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism. PATIENTS AND METHODS The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography. RESULTS Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking for lathosterol by toremifene. Plant sterols and cholestanol were only inconsistently increased in serum. CONCLUSION Tamoxifen and toremifene inhibit the conversion of delta 8-cholestenol to lathosterol so that serum total and LDL cholesterol levels are lowered by downregulation of cholesterol synthesis. Thus, inhibition of the delta 8-isomerase may be the major hypolipidemic effect of these agents. Reduced risk of coronary artery disease will probably occur also during long-term toremifene treatment, because the drug reduces cholesterol and its synthesis, similarly to tamoxifen.
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Lystvan, V., A. Zhmurchuk, and V. Lystvan. "SYNTHESIS OF POTENTIAL LIQUID CRYSTALS WITH CHOLESTEROL FRAGMENT BY WITTIG REACTION." Ukrainian Journal of Natural Sciences, no. 2 (January 28, 2023): 143–54. http://dx.doi.org/10.35433/naturaljournal.2.2023.144-154.
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Liquid crystals are substances that owing to the features of their structure and physical properties are of interest not only as objects for theoretical research, but also significantly important practically due to the possibilities of their effective application in various brunches of industry, medicine, in household etc. Among the known classes of liquid crystals, substances known as cholesterics are an important group.
Cholesteric liquid crystals demonstrate very high optical activity, that significantly exceeds the optical activity of most other known classes of organic compounds. Their ability for appreciable change of color at change of the temperature and environment composition is also practically important.
Among all compounds belonging to the class of cholesterics an important place possess cholesterol derivatives, especially cholesterol esters. Therefore, the elaboration of new methods of their synthesis and the introduction of new functional groups into their molecules are an urgent tasks indeed.
This work is devoted to the investigation of the possibility of synthesis of new cholesterol derivatives, namely cholesteryl esters of unsaturated acids by the Wittig reaction - the interaction of various classes of aldehydes with phosphonium salts, with the intermediate formation of phosphorus ylides - alkylidene phosphoranes. We found that the Wittig reaction is a convenient method for the synthesis of cholesteryl esters of unsaturated carboxylic acids. We have developed methods for the synthesis of potential cholesteric liquid crystals by the Wittig reaction, which use a phosphonium salt containing a cholesterol fragment and corresponding aldehydes. The process proceed without the release of an intermediate compound – alkylidene phosphorane, which reduces the labor intensity of the method.
The application of various aldehydes enables the easily obtaining of cholesteryl esters of unsaturated acids containing various aliphatic, aromatic and heterocyclic fragments in the acid radical. The reaction takes place in mild conditions, without using of high temperatures or aggressive environments. The resulting esters show signs of mesophase formation, which is a confirmation of their liquid crystalline properties.
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Scobey, M. W., F. L. Johnson, and L. L. Rudel. "Delivery of high-density lipoprotein free and esterified cholesterol to bile by the perfused monkey liver." American Journal of Physiology-Gastrointestinal and Liver Physiology 257, no. 4 (October 1, 1989): G644—G652. http://dx.doi.org/10.1152/ajpgi.1989.257.4.g644.
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The movement of cholesterol from high-density lipoproteins (HDL) into bile has been studied using perfused livers from cholesterol-fed African Green monkeys. Mass amounts of HDL were isolated from the plasma of African Green monkeys and were doubly labeled with either 125I-apolipoprotein and [3H]cholesteryl ester or with [3H]cholesteryl ester and [14C]cholesterol. For 3 h of perfusion HDL-free cholesterol was cleared from perfusate at a faster rate than HDL ester cholesterol which, in turn, was cleared at a faster rate than HDL protein. [14C]cholesterol from HDL appeared in biliary bile acids and cholesterol at a higher rate than [3H]esterified cholesterol from HDL. The specific activities of biliary [14C]cholesterol and HDL-free [14C]cholesterol had equilibrated by 60 min of perfusion, although the specific activity of whole liver free [14C]cholesterol was still only 46% of that in bile at 180 min of perfusion. In contrast, the specific activity of total liver free [3H]cholesterol was equal to that of biliary [3H]cholesterol by 180 min of perfusion. We conclude that, in this primate model, HDL-free cholesterol enters into a hepatic compartment that communicates with biliary cholesterol and bile acid precursor pools more efficiently than with other liver pools of cholesterol, whereas HDL-esterified cholesterol appears to mix with all liver pools with equal efficiency. Overall, these data support the concept of compartmentalization of cholesterol in the liver.
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Hallikainen, Maarit, Henri Tuomilehto, Tarja Martikainen, Esko Vanninen, Juha Seppä, Jouko Kokkarinen, Jukka Randell, and Helena Gylling. "Cholesterol Metabolism and Weight Reduction in Subjects with Mild Obstructive Sleep Apnoea: A Randomised, Controlled Study." Cholesterol 2013 (May 16, 2013): 1–9. http://dx.doi.org/10.1155/2013/769457.
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To evaluate whether parameters of obstructive sleep apnoea (OSA) associate with cholesterol metabolism before and after weight reduction, 42 middle-aged overweight subjects with mild OSA were randomised to intensive lifestyle intervention (N=23) or to control group (N=18) with routine lifestyle counselling only. Cholesterol metabolism was evaluated with serum noncholesterol sterol ratios to cholesterol, surrogate markers of cholesterol absorption (cholestanol and plant sterols) and synthesis (cholestenol, desmosterol, and lathosterol) at baseline and after 1-year intervention. At baseline, arterial oxygen saturation (SaO2) was associated with serum campesterol (P<0.05) and inversely with desmosterol ratios (P<0.001) independently of gender, BMI, and homeostasis model assessment index of insulin resistance (HOMA-IR). Apnoea-hypopnoea index (AHI) was not associated with cholesterol metabolism. Weight reduction significantly increased SaO2and serum cholestanol and decreased AHI and serum cholestenol ratios. In the groups combined, the changes in AHI were inversely associated with changes of cholestanol and positively with cholestenol ratios independent of gender and the changes of BMI and HOMA-IR (P<0.05). In conclusion, mild OSA seemed to be associated with cholesterol metabolism independent of BMI and HOMA-IR. Weight reduction increased the markers of cholesterol absorption and decreased those of cholesterol synthesis in the overweight subjects with mild OSA.
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Mayorek, N., and J. Bar-Tana. "Hypocholesterolaemic effect of β β'-methyl-substituted hexadecanedioic acid (MEDICA 16) in the male hamster." Biochemical Journal 289, no. 3 (February 1, 1993): 911–17. http://dx.doi.org/10.1042/bj2890911.
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Treatment of cholesterol-fed male hamsters kept on a diet of purina chow with beta beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) resulted in a progressive hypocholesterolaemic effect, amounting to a 50% decrease in the cholesterol content of all plasma lipoproteins. The decrease in plasma cholesterol could be accounted for by activation of plasma-cholesterol efflux through the liver into the bile mediated by MEDICA 16-induced (a) increase of the number of liver LDL receptors, (b) activation of liver neutral cholesteryl ester hydrolase with a concomitant inhibition of liver acyl-CoA cholesterol acyltransferase, resulting in shifting of the liver cholesteryl ester/free-cholesterol cycle in the direction of free cholesterol, and (c) activation of cholesterol efflux from the liver into the bile. The increase in bile cholesterol output was accompanied by an increase in bile phospholipids but not in bile acids. In contrast with rats, MEDICA 16-treatment of male hamsters did not result in a hypotriacylglycerolaemic effect, inhibition of lipogenesis, nor in a substantial decrease in plasma apolipoprotein C-III content.
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Pincinato, Eder de Carvalho, Patricia Moriel, and Dulcinéia Saes Parra Abdalla. "Cholesterol oxides inhibit cholesterol esterification by lecithin: cholesterol acyl transferase." Brazilian Journal of Pharmaceutical Sciences 45, no. 3 (September 2009): 429–35. http://dx.doi.org/10.1590/s1984-82502009000300007.
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Cholesterol oxides are atherogenic and can affect the activity of diverse important enzymes for the lipidic metabolism. The effect of 7β-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol, cholestan-3β,5α,6β-triol,5,6β-epoxycholesterol, 5,6α-epoxycholesterol and 7α-hydroxycholesterol on esterification of cholesterol by lecithin:cholesterol acyl transferase (LCAT, EC 2.3.1.43) and the transfer of esters of cholesterol oxides from high density lipoprotein (HDL) to low density lipoproteins (LDL) and very low density lipoproteins (VLDL) by cholesteryl ester transfer protein (CETP) was investigated. HDL enriched with increasing concentrations of cholesterol oxides was incubated with fresh plasma as source of LCAT. Cholesterol and cholesterol oxides esterification was followed by measuring the consumption of respective free sterol and oxysterols. Measurements of cholesterol and cholesterol oxides were done by gas-chromatography. 14C-cholesterol oxides were incorporated into HDL2 and HDL3 subfractions and then incubated with fresh plasma containing LCAT and CETP. The transfer of cholesterol oxide esters was followed by measuring the 14C-cholesterol oxide-derived esters transferred to LDL and VLDL. All the cholesterol oxides studied were esterified by LCAT after incorporation into HDL particles, competing with cholesterol by LCAT. Cholesterol esterification by LCAT was inversely related to the cholesterol oxide concentration. The esterification of 14C-cholesterol oxides was higher in HDL3 and the transfer of the derived esters was greater from HDL2 to LDL and VLDL. The results suggest that cholesterol esterification by LCAT is inhibited in cholesterol oxide-enriched HDL particles. Moreover, the cholesterol oxides-derived esters are efficiently transferred to LDL and VLDL. Therefore, we suggest that cholesterol oxides may exert part of their atherogenic effect by inhibiting cholesterol esterification on the HDL surface and thereby disturbing reverse cholesterol transport.
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Klipsic, Devon, Danilo Landrock, Gregory G. Martin, Avery L. McIntosh, Kerstin K. Landrock, John T. Mackie, Friedhelm Schroeder, and Ann B. Kier. "Impact of SCP-2/SCP-x gene ablation and dietary cholesterol on hepatic lipid accumulation." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 5 (September 1, 2015): G387—G399. http://dx.doi.org/10.1152/ajpgi.00460.2014.
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While a high-cholesterol diet induces hepatic steatosis, the role of intracellular sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) proteins is unknown. We hypothesized that ablating SCP-2/SCP-x [double knockout (DKO)] would impact hepatic lipids (cholesterol and cholesteryl ester), especially in high-cholesterol-fed mice. DKO did not alter food consumption, and body weight (BW) gain decreased especially in females, concomitant with hepatic steatosis in females and less so in males. DKO-induced steatosis in control-fed wild-type (WT) mice was associated with 1) loss of SCP-2; 2) upregulation of liver fatty acid binding protein (L-FABP); 3) increased mRNA and/or protein levels of sterol regulatory element binding proteins (SREBP1 and SREBP2) as well as increased expression of target genes of cholesterol synthesis ( Hmgcs1 and Hmgcr) and fatty acid synthesis ( Acc1 and Fas); and 4) cholesteryl ester accumulation was also associated with increased acyl-CoA cholesterol acyltransferase-2 (ACAT2) in males. DKO exacerbated the high-cholesterol diet-induced hepatic cholesterol and glyceride accumulation, without further increasing SREBP1, SREBP2, or target genes. This exacerbation was associated both with loss of SCP-2 and concomitant downregulation of Ceh/Hsl, apolipoprotein B (ApoB), MTP, and/or L-FABP protein expression. DKO diminished the ability to secrete excess cholesterol into bile and oxidize cholesterol to bile acid for biliary excretion, especially in females. This suggested that SCP-2/SCP-x affects cholesterol transport to particular intracellular compartments, with ablation resulting in less to the endoplasmic reticulum for SREBP regulation, making more available for cholesteryl ester synthesis, for cholesteryl-ester storage in lipid droplets, and for bile salt synthesis and/or secretion. These alterations are significant findings, since they affect key processes in regulation of sterol metabolism.
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Whyte, Martin B. "Is high-density lipoprotein a modifiable treatment target or just a biomarker for cardiovascular disease?" JRSM Cardiovascular Disease 8 (January 2019): 204800401986973. http://dx.doi.org/10.1177/2048004019869736.
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Epidemiological data strongly support the inverse association between high-density lipoprotein cholesterol concentration and cardiovascular risk. Over the last three decades, pharmaceutical strategies have been partially successful in raising high-density lipoprotein cholesterol concentration, but clinical outcomes have been disappointing. A recent therapeutic class is the cholesteryl ester transfer protein inhibitor. These drugs can increase circulating high-density lipoprotein cholesterol levels by inhibiting the exchange of cholesteryl ester from high-density lipoprotein for triacylglycerol in larger lipoproteins, such as very low-density lipoprotein and low-density lipoprotein. Recent trials of these agents have not shown clinical benefit. This article will review the evidence for cardiovascular risk associated with high-density lipoprotein cholesterol and discuss the implications of the trial data for cholesteryl ester transfer protein inhibitors.
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Slotte, J. P., and E. L. Bierman. "Depletion of plasma-membrane sphingomyelin rapidly alters the distribution of cholesterol between plasma membranes and intracellular cholesterol pools in cultured fibroblasts." Biochemical Journal 250, no. 3 (March 15, 1988): 653–58. http://dx.doi.org/10.1042/bj2500653.
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This study examines the relationship between cellular sphingomyelin content and the distribution of unesterified cholesterol between the plasma-membrane pool and the putative intracellular regulatory pool. The sphingomyelin content of cultured human skin fibroblasts was reduced by treatment of intact cells with extracellularly added neutral sphingomyelinase, and subsequent changes in the activities of cholesterol-metabolizing enzymes were determined. Exposure of fibroblasts to 0.1 unit of sphingomyelinase/ml for 60 min led to the depletion of more than 90% of the cellular sphingomyelin, as determined from total lipid extracts. In a time-course study, it was found that within 10 min of the addition of sphingomyelinase to cells, a dramatic increase in acyl-CoA:cholesterol acyltransferase activity could be observed, whether measured from the appearance of plasma membrane-derived [3H]cholesterol or exogenously added [14C]oleic acid, in cellular cholesteryl esters. In addition, the cholesteryl ester mass was significantly higher in sphingomyelin-depleted fibroblasts at 3 h after exposure to sphingomyelinase compared with that in untreated fibroblasts [7.1 +/- 0.4 nmol of cholesterol/mg equivalents of esterified cholesterol compared with 4.2 +/- 0.1 nmol of cholesterol/mg equivalents of cholesteryl ester in control cells (P less than 0.05)]. The sphingomyelin-depleted cells also showed a reduction in the rate of endogenous synthesis of cholesterol, as measured by incorporation of sodium [14C]acetate into [14C]cholesterol. These results are consistent with a rapid movement of cholesterol from sphingomyelin-depleted plasma membranes to the putative intracellular regulatory pool of cholesterol. This mass movement of cholesterol away from the plasma membranes presumably resulted from a decreased capacity of the plasma membranes to solubilize cholesterol, since sphingomyelin-depleted cells also had a decreased capacity to incorporate nanomolar amounts of [3H]cholesterol from the extracellular medium, as compared with control cells. These findings confirm previous assumptions that the membrane sphingomyelin content is an important determinant of the overall distribution of cholesterol within intact cells.
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Nagy, L., and D. A. Freeman. "Cholesterol movement between the plasma membrane and the cholesteryl ester droplets of cultured Leydig tumour cells." Biochemical Journal 271, no. 3 (November 1, 1990): 809–14. http://dx.doi.org/10.1042/bj2710809.
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The present studies characterize the turnover of plasma membrane cholesterol in MA-10 Leydig tumour cells. Plasma membrane cholesterol of MA-10 cells was slowly internalized and converted into cholesteryl ester. Low-density lipoprotein (LDL) stimulated, in a dose- and time-dependent fashion, plasma membrane cholesterol conversion into intracellular esters. Stimulation of membrane internalization was not simply the consequence of accelerated uptake of membrane with LDL, since binding and internalization of epidermal growth factor and transferrin had no effect on turnover of plasma membrane cholesterol. The protein of LDL is unimportant as well, since delipidated LDL had no effect on membrane turnover. The action of LDL on cholesterol turnover was explained entirely by its contribution to cholesteryl ester stores. The degree of plasma membrane cholesterol internalization and esterification was directly proportional to the size of cellular ester stores.
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Bindu Madhavi, A., and S. Sreehari Sastry. "Rheological properties of cholesteric liquid crystals as lubricant additives." International Journal of Modern Physics B 33, no. 05 (February 20, 2019): 1950014. http://dx.doi.org/10.1142/s0217979219500140.
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Rheological properties of Cholesteryl n-valerate, Cholesteryl decanoate and Cholesteryl myristate which are esters of cholesterol have been studied. Phase transition temperatures and rheological parameters such as viscosity, elastic modulus G[Formula: see text], loss modulus G[Formula: see text] as functions of temperature, shear rate and time are investigated. In frequency sweep test, a higher transition crossover region has occurred for Cholesteryl myristate, whereas for Cholesteryl n-valerate a frequency-independent plateau prevailed for both the moduli. The occurrence of blue phase in Cholesteryl decanoate during temperature sweep measurements is an indication for the rheological support. The results for steady state have informed that cholesteric esters are having non-Newtonian flow behavior in their respective cholesteric phases. The power-law model has explained well the shear rate dependence of shear stress. A few practical applications of these esters as lubricant additives are discussed, too.
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Bouillet, Benjamin, Thomas Gautier, Damien Denimal, Maxime Samson, David Masson, Jean Paul Pais de Barros, Guillaume Maquart, et al. "Glucocorticoids impair HDL-mediated cholesterol efflux besides increased HDL cholesterol concentration: a proof of concept." European Journal of Endocrinology 183, no. 3 (September 2020): 297–306. http://dx.doi.org/10.1530/eje-20-0477.
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Objective: Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC. Design: Prospective, observational study. Methods: Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice. Results: In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively). Conclusions: We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.
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Goel, Vinti, Sukhinder K. Cheema, Luis B. Agellon, Buncha Ooraikul, and Tapan K. Basu. "Dietary rhubarb (Rheum rhaponticum) stalk fibre stimulates cholesterol 7α-hydroxylase gene expression and bile acid excretion in cholesterol-fed C57BL/6J mice." British Journal of Nutrition 81, no. 1 (January 1999): 65–71. http://dx.doi.org/10.1017/s0007114599000161.
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Both experimental and clinical studies have indicated that a novel source of dietary fibre, produced from rhubarb (Rheum rhaponticum) stalks, is potentially hypolipidaemic. The present study, using C57BL/6J mice, was undertaken to examine if this fibre source affects cholesterol degradation. Mice were maintained on semi-purified diets containing 50 g rhubarb fibre or cellulose/kg with or without 5 g cholesterol/kg for 4 weeks. In cholesterol-supplemented mice, rhubarb fibre caused significant lowering of plasma cholesterol (-13 %) and the hepatic concentrations of total cholesterol (-34 %) and cholesteryl esters (-34 %). In parallel to the reduction of hepatic cholesteryl ester content, animals fed on rhubarb fibre had significantly lower activity of acyl CoA: cholesterol acyltransferase (EC 2.3.1.26) than the mice maintained on a diet containing cellulose and cholesterol. Rhubarb-fibre feeding accelerated the faecal bile-acid loss and diminished the gall-bladder bile-acid pool in both the normal and the cholesterol-fed mice. The increase in the bile-acid excretion was positively correlated with an increased activity as well as mRNA abundance of cholesterol 7α-hydroxylase (EC 1.14.13.17). The increased excretion of bile acids and induction of cholesterol 7α-hydroxylase activity may account for the hypocholesterolaemic effect of rhubarb fibre.
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Meijer, G. W., P. N. M. Demacker, A. Van Tol, J. E. M. Groener, J. G. P. Van der Palen, A. F. H. Stalenhoef, L. M. F. Van Zutphen, and A. C. Beynen. "Plasma activities of lecithin:cholesterol acyltransferase, lipid transfer proteins and post-heparin lipases in inbred strains of rabbits hypo- or hyper-responsive to dietary cholesterol." Biochemical Journal 293, no. 3 (August 1, 1993): 729–34. http://dx.doi.org/10.1042/bj2930729.
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Plasma lipoproteins, plasma activities of lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP) and post-heparin lipases were measured before and after cholesterol challenge in two inbred strains of rabbits with either a high (hyper-responders) or a low (hyporesponders) response of plasma cholesterol to dietary cholesterol. The purpose of this study was to provide clues about the mechanisms underlying the effect of dietary cholesterol on lipoprotein levels and composition, and particularly those underlying the strain difference of this effect. Cholesterol feeding (0.15 g of cholesterol/100 g of diet) caused increased plasma total cholesterol concentrations and an increased ratio of cholesteryl esters:triacylglycerol in all lipoprotein particles in both strains; these effects were significantly greater in hyper- than hypo-responsive rabbits. Feeding on the high-cholesterol diet lowered plasma triacylglycerols in hyper-responders, but caused increased plasma triacylglycerol levels in hyporesponders. This was accompanied by significantly greater increases in the activities of hepatic triacylglycerol lipase and lipoprotein lipase in hyper- than in hypo-responders. Both strains showed a dietary-cholesterol-induced rise in plasma CETP as well as in PLTP activity. The increase in PLTP activity was greater in the hyper-responders, but that of CETP was less. There was no effect of dietary cholesterol on LCAT activity. It is hypothesized that the lipases are involved in the removal of cholesterol-rich lipoproteins.
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Cheng, W., K. V. Kvilekval, and N. A. Abumrad. "Dexamethasone enhances accumulation of cholesteryl esters by human macrophages." American Journal of Physiology-Endocrinology and Metabolism 269, no. 4 (October 1, 1995): E642—E648. http://dx.doi.org/10.1152/ajpendo.1995.269.4.e642.
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The effects of dexamethasone on lipid accumulation by human monocyte-derived macrophages were investigated. Preincubation of macrophages with dexamethasone for a period of 16-20 h resulted in a reproducible increase (3.5-fold) in the incorporation of oleate into cholesteryl esters. The effect was specific because no alterations were observed in oleate incorporation into triglycerides or phospholipids. Measurement of cellular cholesteryl esters indicated a fourfold increase after preincubation with dexamethasone. This increase was mediated by opposite effects on synthesis and breakdown of these lipids. Dexamethasone produced a 60% increase in activity of the enzyme acyl-CoA: cholesterol O-acyltransferase (ACAT), active in synthesis of cholesteryl esters, and a 40% decrease in that of neutral cholesteryl esterase, active in cholesteryl ester breakdown. The increased ACAT activity appeared to reflect increased mRNA for the enzyme. The effects of dexamethasone on cholesteryl ester accumulation by macrophages reached statistical significance at a concentration of 100 nM. They were dose dependent, and saturation was observed at around 1 microM. The effects were significant at low concentrations of cholesterol in the medium. At high-medium cholesterol, there was a large cholesterol-induced increase in ACAT activity that obscured most of the effect of dexamethasone. In general, the data suggest that high glucocorticoid levels enhance lipid accumulation by macrophages and thus would have an atherogenic action that is independent of serum cholesterol.
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Lagace, Thomas A. "Phosphatidylcholine: Greasing the Cholesterol Transport Machinery." Lipid Insights 8s1 (January 2015): LPI.S31746. http://dx.doi.org/10.4137/lpi.s31746.
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Negative feedback regulation of cholesterol metabolism in mammalian cells ensures a proper balance of cholesterol with other membrane lipids, principal among these being the major phospholipid phosphatidylcholine (PC). Processes such as cholesterol biosynthesis and efflux, cholesteryl ester storage in lipid droplets, and uptake of plasma lipoproteins are tuned to the cholesterol/PC ratio. Cholesterol-loaded macrophages in atherosclerotic lesions display increased PC biosynthesis that buffers against elevated cholesterol levels and may also facilitate cholesterol trafficking to enhance cholesterol sensing and efflux. These same mechanisms could play a generic role in homeostatic responses to acute changes in membrane free cholesterol levels. Here, I discuss the established and emerging roles of PC metabolism in promoting intracellular cholesterol trafficking and membrane lipid homeostasis.
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Adams, Michelle R., Eddy Konaniah, James G. Cash, and David Y. Hui. "Use of NBD-cholesterol to identify a minor but NPC1L1-independent cholesterol absorption pathway in mouse intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 300, no. 1 (January 2011): G164—G169. http://dx.doi.org/10.1152/ajpgi.00392.2010.
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The importance of Niemann-Pick C1 Like-1 (NPC1L1) protein in intestinal absorption of dietary sterols, including both cholesterol and phytosterols, is well documented. However, the exact mechanism by which NPC1L1 facilitates cholesterol transport remains controversial. This study administered 22-( N(-7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol) and [3H]cholesterol to Npc1l1+/+ and Npc1l1−/− mice to determine whether NPC1L1 facilitates dietary sterol uptake by enterocytes and/or participates in intracellular sterol delivery to the endoplasmic reticulum (ER) for lipoprotein assembly before secretion into plasma circulation. Results showed that [3H]cholesterol absorption was reduced but not abolished in Npc1l1−/− mice compared with Npc1l1+/+ mice. In the presence of Pluronic L-81 to block pre-chylomicron exit from the ER, significant amounts of [3H]cholesterol were found to be associated with lipid droplets in the intestinal mucosa of both Npc1l1+/+ and Npc1l1−/− mice, and the intracellular [3H]cholesterol can be esterified to cholesteryl esters. These results provided evidence indicating that the main function of NPC1L1 is to promote cholesterol uptake from the intestinal lumen but that it is not necessary for intracellular cholesterol transport to the ER. Surprisingly, NBD-cholesterol was taken up by intestinal mucosa, esterified to NBD-cholesteryl esters, and transported to plasma circulation to similar extent between Npc1l1+/+ and Npc1l1−/− mice. Ezetimibe treatment also had no impact on NBD-cholesterol absorption by Npc1l1+/+ mice. Thus, NBD-cholesterol absorption proceeds through an NPC1L1-independent and ezetimibe-insensitive sterol absorption mechanism. Taken together, these results indicate that NBD-cholesterol can be used to trace the alternative cholesterol absorption pathway but is not suitable for tracking NPC1L1-mediated cholesterol absorption.
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Clark, Richard M., and Kenneth E. Hundrieser. "Changes in Cholesteryl Esters of Human Milk with Total Milk Lipid." Journal of Pediatric Gastroenterology and Nutrition 9, no. 3 (October 1989): 347–50. http://dx.doi.org/10.1002/j.1536-4801.1989.tb09881.x.
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Twenty‐five milk samples with a wide range of total lipid and degree of fatty acid saturation were chosen for this study. The milk samples were analyzed for total lipid, total cholesterol, and free cholesterol. The cholesteryl esters and triacylglycerols in these samples also were isolated and the fatty acids associated with each lipid class determined. Total cholesterol averaged 13.5 ± 3.1 mg/dl of milk and was significantly correlated (r = 0.60, p < 0.05) with total lipid. Free cholesterol averaged 10.9 ‡ 2.3 mg/dl of milk and also was significantly correlated (r = 0.72, p < 0.05) with total lipid. As total milk lipid increased, the fatty acids in cholesteryl esters became more saturated. The fatty acids most affected were 18:2 and 20:4. Total milk lipid and 18:2 in cholesteryl esters were inversely related (r = −0.49, p < 0.05). There was also a negative correlation (r = −0.51, p < 0.05) between 20:4 in cholesteryl esters and total lipid. The fatty acids in triacylglycerol were not correlated with total lipid. From these results it appears that the fatty acids esterified to cholesterol and triacylglycerol in milk may be drawn from different substrate pools.
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Kam, N. T., E. Albright, S. Mathur, and F. J. Field. "Effect of lovastatin on acyl-CoA: cholesterol O-acyltransferase (ACAT) activity and the basolateral-membrane secretion of newly synthesized lipids by CaCo-2 cells." Biochemical Journal 272, no. 2 (December 1, 1990): 427–33. http://dx.doi.org/10.1042/bj2720427.
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Lovastatin, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity, was used to study the regulation of cholesterol metabolism and the basolateral-membrane secretion of triacylglycerol and cholesterol in the human intestinal cell line CaCo-2. At 0.1 microgram/ml, lovastatin decreased 3H2O incorporation into cholesterol by 71%. In membranes prepared from cells incubated with lovastatin for 18 h, HMG-CoA reductase activity was induced 4-8-fold. Mevalonolactone prevented this induction. In intact cells, lovastatin (10 micrograms/ml) decreased cholesterol esterification by 50%. The reductase inhibitor decreased membrane acyl-CoA:cholesterol O-acyltransferase (ACAT) activity by 50% at 5 micrograms/ml. ACAT inhibition by lavastatin was not reversed by adding excess of cholesterol or fatty acyl-CoA to the assay. Lovastatin, in the presence or absence of mevalonolactone, decreased the basolateral secretion of newly synthesized cholesteryl esters and triacylglycerols. Lovastatin also inhibited the esterification of absorbed cholesterol and the secretion of this newly synthesized cholesteryl ester. Lovastatin is a potent inhibitor of cholesterol synthesis in CaCo-2 cells. Moreover, it is a direct inhibitor of ACAT activity, independently of its effect on HMG-CoA reductase and cholesterol synthesis.
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GELISSEN, Ingrid C., Tim HOCHGREBE, Mark R. WILSON, Simon B. EASTERBROOK-SMITH, Wendy JESSUP, Roger T. DEAN, and Andrew J. BROWN. "Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function?" Biochemical Journal 331, no. 1 (April 1, 1998): 231–37. http://dx.doi.org/10.1042/bj3310231.
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Apolipoprotein J (apo J) is a secreted glycoprotein of which the exact function remains a matter for speculation. Apo J has been implicated in such diverse processes as sperm maturation, regulation of complement activation, programmed cell death, tissue remodelling and lipid transport. In this study a possible role for apo J in lipid transport was explored. Mouse peritoneal macrophages were incubated with acetylated low-density lipoprotein (AcLDL) to produce foam cells containing cholesterol and cholesteryl esters. Incubation of the foam cells with physiological concentrations of purified apo J led to a dose-dependent export of cholesterol. The appearance of cholesterol in the medium was associated predominantly with a decline in intracellular cholesteryl esters rather than intracellular free cholesterol. The kinetics of cholesterol release to apo J were similar to apo A-I, an established promoter of cholesterol efflux. Apo J was also shown to induce phospholipid efflux from cells, whereas the cholesterol exported to the medium was associated with the apo J. Studies using foam cells from apo E-null mice showed that the cholesterol exported to the medium was independent of apo E production by the cells. These results present the first evidence that apo J can promote cholesterol efflux from foam cells and indicates that it might have a function in cellular cholesterol homoeostasis in both normal and pathological situations.
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Mindham, M. A., and P. A. Mayes. "Application of simultaneous spleen and liver perfusion to the study of reverse cholesterol transport." Biochemical Journal 302, no. 1 (August 15, 1994): 207–13. http://dx.doi.org/10.1042/bj3020207.
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1. A new method to isolate and perfuse the rat spleen and liver simultaneously with a common blood perfusate at high haematocrit was developed. The spleen was pre-labelled with [3H]cholesterol, enabling reverse cholesterol transport from an extrahepatic tissue to the blood and thence to the liver and bile to be studied in a single preparation in vitro. 2. The presence of the liver significantly increased the release of [3H]cholesterol from the spleen by 15%, compared with experiments where the spleen was perfused alone. 3. There was a substantial release of [3H]cholesterol and cholesterol mass from the spleen to serum lipoproteins, the majority (80%) to high-density lipoprotein (HDL), in which cholesteryl ester accumulated. 4. The HDL subfractions HDL2 and HDL3 (d 1.085-1.250) were most important for removal of cholesterol from the spleen, whereas HDL1 and HDL2 (d 1.050-1.125) were important for delivery of cholesterol to the liver, a net uptake of cholesteryl ester occurring only from these fractions. 5. Approximately half of the [3H]cholesterol released by the spleen was recovered in erythrocytes. Also, in experiments utilizing a lipoprotein-free perfusate containing erythrocytes, a substantial quantity of [3H]cholesterol was transported and/or exchanged into the liver and bile, indicating that erythrocytes play an important role in the equilibration of unesterified cholesterol between the tissues.
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Mathur, S. N., E. Albright, and F. J. Field. "Incorporation of lipoxygenase products into cholesteryl esters by acyl-CoA:cholesterol acyltransferase in cholesterol-rich macrophages." Biochemical Journal 256, no. 3 (December 15, 1988): 807–14. http://dx.doi.org/10.1042/bj2560807.
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Macrophages which were incubated with acetylated low-density lipoproteins, resulting in cholesteryl ester accumulation, incorporated the monohydroxyeicosatetraenoic acids (5-, 15-, and 12-HETEs) into cholesteryl esters. The esterification of these hydroxy fatty acids to cholesterol by total membrane preparations of cholesterol-rich macrophages was dependent on the synthesis of the fatty acyl-CoA derivative, and was catalysed by acyl-CoA:cholesterol acyltransferase (ACAT). Stimulation of membrane ACAT activity by 25-hydroxycholesterol increased the synthesis of cholesteryl 12-HETE by 40%. In contrast, inhibiting ACAT activity by progesterone and compound 58-035 decreased cholesteryl 12-HETE production by 60% and 90% respectively. Although 5-, 15- and 12-HETE were esterified to cholesterol by ACAT, these monohydroxy fatty acids were less optimal as substrates compared with oleic acid or arachidonic acid. The hydrolysis and release of 12-HETE and the other monohydroxyeicosatetraenoic acids from intracellular cholesteryl esters and phospholipids occurred at a faster rate than for the more conventional fatty acids, oleate and arachidonate. Cholesteryl esters which contain hydroxy fatty acids therefore provide only a transient storage for lipoxygenase products, as these fatty acids are released into the medium as readily as hydroxy fatty acids found in phospholipids and triacylglycerols. The data provide evidence, for the first time, of an ACAT-dependent esterification of the lipoxygenase products 5-, 15- and 12-HETEs to cholesterol in the macrophage-derived foam cell. The channelling of these monohydroxy fatty acids to cholesteryl esters provides a mechanism which can alter the amount of lipoxygenase products incorporated into cellular phospholipids, thus averting deleterious changes to cell membranes. ACAT, by catalysing the esterification of monohydroxyeicosatetraenoic acids to cholesterol, could play a key role in regulating the amount of lipoxygenase products in the pericellular space of the cholesterol-enriched macrophage.
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Borthwick, Faye, Anne-Marie Allen, Janice M. Taylor, and Annette Graham. "Overexpression of STARD3 in human monocyte/macrophages induces an anti-atherogenic lipid phenotype." Clinical Science 119, no. 7 (June 22, 2010): 265–72. http://dx.doi.org/10.1042/cs20100266.
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Dysregulated macrophage cholesterol homoeostasis lies at the heart of early and developing atheroma, and removal of excess cholesterol from macrophage foam cells, by efficient transport mechanisms, is central to stabilization and regression of atherosclerotic lesions. The present study demonstrates that transient overexpression of STARD3 {START [StAR (steroidogenic acute regulatory protein)-related lipid transfer] domain 3; also known as MLN64 (metastatic lymph node 64)}, an endosomal cholesterol transporter and member of the ‘START’ family of lipid trafficking proteins, induces significant increases in macrophage ABCA1 (ATP-binding cassette transporter A1) mRNA and protein, enhances [3H]cholesterol efflux to apo (apolipoprotein) AI, and reduces biosynthesis of cholesterol, cholesteryl ester, fatty acids, triacylglycerol and phospholipids from [14C]acetate, compared with controls. Notably, overexpression of STARD3 prevents increases in cholesterol esterification in response to acetylated LDL (low-density lipoprotein), blocking cholesteryl ester deposition. Thus enhanced endosomal trafficking via STARD3 induces an anti-atherogenic macrophage lipid phenotype, positing a potentially therapeutic strategy.
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Hussain, Shabbir, Safdar Amir, and Naureen Naeem. "Nature and Effects of Cholesterol; Its Origin, Metabolism and Characterization." Lahore Garrison University Journal of Life Sciences 3, no. 4 (April 22, 2020): 196–203. http://dx.doi.org/10.54692/lgujls.2019.030465.
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Cholesterol ((3β)-cholest-5-en-3-ol) is basically a fatty component present in blood, plasma and tissues. It belongs to the class of lipids namely steroids and is formed from squalene via lanosterol. It is present as a combination of cholesterol and cholesteryl esters in almost all types of foodstuffs. There is the direct relation between the risk of cardiovascular sicknesses and the total cholesterol amount in human blood. The bad- and good-cholesterol are types of lipoproteins. Good-cholesterol basically eliminates cholesterol from bloodstream while bad-cholesterol releases cholesterol into the blood and various part of body. Cholesterol amount can be reduced by physical activity or by use of proper diet. Cholesterol can be characterized by the SIM-selected ion monitoring, HPLC, UHPLC, GLC, GC-MS, LC-MS.
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Tsujita, Maki. "Research on novel HDL cholesterol excretion mechanism." Impact 2023, no. 3 (September 21, 2023): 43–45. http://dx.doi.org/10.21820/23987073.2023.3.43.
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Too much cholesterol can lead to health problems but cholesterol on high-density lipoprotein (HDL-C) is sometimes referred to as `good´ cholesterol because it is inversely related to cardiovascular disease risk. Junior Associate Professor Maki Tsujita, Department of Biochemistry, Nagoya City University, Japan, is leading a team of researchers conducting studies on the novel high-density lipoprotein (HDL) cholesterol excretion mechanism with a view to obtaining new insights on the link between lipid metabolism and diet. Cholesterol biosynthesis involves more than 30 biosynthetic steps and the body has an efficient absorption mechanism to acquire it from the diet via NPC1L1 in the small intestine. The cholesteryl ester transfer protein (CETP) acts as a key recycling mechanism for cholesterol that mediates the equilibrium of cholesteryl esters (CE), limiting cholesterol excretion. The focus of Tsujita's research is on the movement of free-cholesterol molecules and examining its excretion from the body. Tsujita' wants to clarify whether it is CE or free cholesterol that the SR-B1 receptor takes into the cell when it binds HDL, in order to better understand the details of the metabolism of cholesterol. In her current study, she is using a new approach to investigating the origin of free cholesterol in plasma and has found that radiolabelled FCs are increased in SR-BI deficient mice compared to wild-type mice, suggesting that the conversion of CE to FCs is occurring in the blood.
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Goyenechea, Estibaliz, Laura J. Collins, Dolores Parra, Gaifen Liu, Harold Snieder, Ramasamyiyer Swaminathan, Tim D. Spector, J. Alfredo Martínez, and Sandra D. O'Dell. "CD36Gene Promoter Polymorphisms Are Associated With Low Density Lipoprotein-Cholesterol in Normal Twins and After a Low-Calorie Diet in Obese Subjects." Twin Research and Human Genetics 11, no. 6 (December 1, 2008): 621–28. http://dx.doi.org/10.1375/twin.11.6.621.
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AbstractCommon polymorphisms of theCD36fatty acid transporter gene have been associated with lipid metabolism and cardiovascular disease. Association of aCD36promoter single nucleotide polymorphism genotype with anthropometry and serum lipids was investigated in normal subjects, and in obese subjects during an 8-week low calorie diet and 6-month weight-maintenance period. 2728 normal female Twins UK subjects (mean body mass index 24.8 ± 4.4 kg/m2; age 47.3 ± 12.5 y) and 183 obese male and female Spanish subjects (mean body mass index 30.6 ± 3.0 kg/m2; age 35.0 ± 5.0 y) were genotyped for theCD36-22674T/C(rs2151916) promoter single nucleotide polymorphism. In the Twins UK full cohort, theC-allele was associated with lower low density lipoprotein-cholesterol (p= .02,N= 2396). No associations were found in the obese Spanish subjects at baseline, but 6 months after the end of the low-calorie diet, theC-allele was associated with lower total- (p= .03) and low density lipoprotein-cholesterol (p= .01) and higher high density lipoprotein-cholesterol (p= .01). Intake of saturated fatty acids was lower in carriers of theC-allele at baseline, but not significantly so (p= .11). However, 6 months after the end of the low-calorie diet, elements of the lipid profile were correlated with saturated fatty acid intake: total cholesterolr= .21,p= .060; low density lipoprotein-cholesterol:r= .25,p= .043; high density lipoprotein-cholesterol:r= –.26,p= .007.CD36promoter SNP allele –22674Cis therefore associated with lower serum low-density lipoprotein-cholesterol in normal female twins and with improved lipid profile during weight loss and maintenance in obese subjects.
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Rajaram, O. V., R. Y. S. Chan, and W. H. Sawyer. "Effect of unesterified cholesterol on the activity of cholesteryl ester transfer protein." Biochemical Journal 304, no. 2 (December 1, 1994): 423–30. http://dx.doi.org/10.1042/bj3040423.
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Cholesteryl ester transfer protein (CETP) catalyses the transfer of cholesteryl ester from high-density lipoprotein to triacylglycerol-rich lipoproteins and the transfer of triacylglycerols in the reverse direction. The activity of CETP has been studied using a continuous fluorescence assay which measures the excimer fluorescence of cholesteryl 1-pyrene decanoate in a synthetic donor microemulsion as the indicator of cholesteryl ester transfer. Emulsions were composed of cholesteryl oleate and egg phosphatidylcholine and had an average particle size of 14 +/- 1 nm as calculated from the molar volume of the components. The effect of changing the physical state of the emulsion surface was examined by including unesterified cholesterol in the donor and acceptor particles. The rate of CETP-induced transfer of the fluorescent cholesteryl ester between microemulsion particles increased when unesterified cholesterol was present at concentrations up to 17 mol% relative to phospholipid. The presence of cholesterol also changed the exchange kinetics from an apparent single-exponential to a double-exponential phenomenon. Binding of CETP to the emulsion surface was accompanied by an enhancement of fluorescence which was used to measure the binding equilibria. The enhancement of exchange due to the presence of cholesterol did not correlate with any increased binding of CETP to the emulsion surface. The presence of unesterified cholesterol in the donor did not affect the rate of transfer of the fluorescent cholesteryl ester when unlabelled emulsion was replaced by high-density lipoprotein as the acceptor. The studies demonstrate the use of microemulsions of defined size and composition for the study of the mechanism of action of CETP.
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Zhao, Bin, Jingmei Song, Richard W. St. Clair, and Shobha Ghosh. "Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages." American Journal of Physiology-Cell Physiology 292, no. 1 (January 2007): C405—C412. http://dx.doi.org/10.1152/ajpcell.00306.2006.
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Reduction of the lipid burden of atherosclerotic lesion-associated macrophage foam cells is a logical strategy to reduce the plaque volume. Since extracellular cholesterol acceptor-mediated cholesterol efflux is the only recognized mechanism of cholesterol removal from foam cells and this process is rate limited at the level of intracellular cholesterol ester hydrolysis, a reaction catalyzed by neutral cholesteryl ester hydrolase (CEH), we examined the hypothesis that CEH overexpression in the human macrophage monocyte/macrophage cell line THP1 results in increased cholesterol efflux, as well as decreased cellular cholesterol ester accumulation. We generated THP1-CEH cells with stable integration of human macrophage CEH cDNA driven by the cytomegalovirus promoter. Compared with wild-type THP1 cells (THP1-WT), THP1-CEH cells showed increased CEH mRNA expression and increased CEH activity. Efflux of free or unesterified cholesterol by acetylated LDL-loaded THP1-CEH cells to ApoA-I by an ABCA1-dependent pathway or to HDL by an ABCG1-dependent pathway was significantly higher than that in THP1-WT cells. In addition, THP1-CEH cells accumulated significantly lower amount of esterified cholesterol. CEH overexpression, therefore, not only enhances cholesterol efflux but also reduces cellular accumulation of cholesteryl esters. Taken together, these data provide evidence for evaluating CEH expression in human macrophages as a potential target for attenuation of foam cell formation and regression of atherosclerotic plaques.
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He, Peng, Shannon Faris, Reddy Sudheer Sagabala, Payel Datta, Zihan Xu, Brian Callahan, Chunyu Wang, Benoit Boivin, Fuming Zhang, and Robert J. Linhardt. "Cholesterol Chip for the Study of Cholesterol–Protein Interactions Using SPR." Biosensors 12, no. 10 (September 25, 2022): 788. http://dx.doi.org/10.3390/bios12100788.
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Cholesterol, an important lipid in animal membranes, binds to hydrophobic pockets within many soluble proteins, transport proteins and membrane bound proteins. The study of cholesterol–protein interactions in aqueous solutions is complicated by cholesterol’s low solubility and often requires organic co-solvents or surfactant additives. We report the synthesis of a biotinylated cholesterol and immobilization of this derivative on a streptavidin chip. Surface plasmon resonance (SPR) was then used to measure the kinetics of cholesterol interaction with cholesterol-binding proteins, hedgehog protein and tyrosine phosphatase 1B.
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Fernandez, Céline, Marie Lindholm, Morten Krogh, Stéphanie Lucas, Sara Larsson, Peter Osmark, Karin Berger, et al. "Disturbed cholesterol homeostasis in hormone-sensitive lipase-null mice." American Journal of Physiology-Endocrinology and Metabolism 295, no. 4 (October 2008): E820—E831. http://dx.doi.org/10.1152/ajpendo.90206.2008.
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Transcriptomics analysis revealed that genes involved in hepatic de novo cholesterol synthesis were downregulated in fed HSL-null mice that had been on a high-fat diet (HFD) for 6 mo. This finding prompted a further analysis of cholesterol metabolism in HSL-null mice, which was performed in fed and 16-h-fasted mice on a normal chow diet (ND) or HFD regimen. Plasma cholesterol was elevated in HSL-null mice, in all tested conditions, as a result of cholesterol enrichment of HDL and VLDL. Hepatic esterified cholesterol content and ATP-binding cassette transporter A1 (ABCA1) mRNA and protein levels were increased in HSL-null mice regardless of the dietary regimen. Unsaturated fatty acid composition of hepatic triglycerides was modified in fasted HSL-null mice on ND and HFD. The increased ABCA1 expression had no major effect on cholesterol efflux from HSL-null mouse hepatocytes. Taken together, the results of this study suggest that HSL plays a critical role in the hydrolysis of cytosolic cholesteryl esters and that increased levels of hepatic cholesteryl esters, due to lack of action of HSL in the liver, are the main mechanism underlying the imbalance in cholesterol metabolism in HSL-null mice.
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Nugraheni, Kartika, and Siti Harnina Bintari. "Aktivitas antidislipidemia Tepung tempe dan susu kedelai pada profil lipid tikus diabetes yang diinduksi streptozotocin." Jurnal Gizi dan Dietetik Indonesia (Indonesian Journal of Nutrition and Dietetics) 4, no. 3 (May 22, 2017): 147. http://dx.doi.org/10.21927/ijnd.2016.4(3).147-153.
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<p><strong>ABSTRACT</strong></p><p><strong>Background :</strong> dyslipidemia increases risk of cardiovascular disease on diabetes patients. Soybean contain many bioactive compounds which can help control lipid profile.</p><p><strong>Objectives :</strong> analyze the difference between fermented soybean (tempe flour) and unfermented soybean (soymilk) on lipid profile in diabetic rats.</p><p><strong>Methods : </strong>thirty male sprague dawley rats divided into 3 groups (1) diabetic control (2) tempe flour 1,8 gr (3) soymilk 1,35 gr. Tempe flour and soymilk were given for 28 days. Profile lipid measured including total cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. The data then were analyzed using Anova with confidence level of 95%.</p><p><strong>Results :</strong> the decrease values of total cholesteril, triglycerides and LDL cholesterol were better in tempe flour group (p<0,05). In addition, tempe flour group also showed better increase in the value of HDL cholesterl (p<0,05)</p><strong>Conclusion :</strong>fermented soybean (tempe flour) showed better antidyslipidemic activity than unfermented ones<p> </p>
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Li, Jianing, Sonja S. Pijut, Yuhuan Wang, Ailing Ji, Rupinder Kaur, Ryan E. Temel, Deneys R. van der Westhuyzen, and Gregory A. Graf. "Simultaneous Determination of Biliary and Intestinal Cholesterol Secretion Reveals That CETP (Cholesteryl Ester Transfer Protein) Alters Elimination Route in Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 39, no. 10 (October 2019): 1986–95. http://dx.doi.org/10.1161/atvbaha.119.312952.
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Objective: Determine the impact of CETP (cholesteryl ester transfer protein) on the route of cholesterol elimination in mice. Approach and Results: We adapted our protocol for biliary cholesterol secretion with published methods for measuring transintestinal cholesterol elimination. Bile was diverted and biliary lipid secretion maintained by infusion of bile acid. The proximal small bowel was perfused with bile acid micelles. In high-fat, high-cholesterol–fed mice, the presence of a CETP transgene increased biliary cholesterol secretion at the expense of transintestinal cholesterol elimination. The increase in biliary cholesterol secretion was not associated with increases in hepatic SR-BI (scavenger receptor BI) or ABCG5 (ATP-binding cassette G5) ABCG8. The decline in intestinal cholesterol secretion was associated with an increase in intestinal Niemann-Pick disease, type C1, gene-like 1 mRNA. Finally, we followed the delivery of HDL (high-density lipoprotein) or LDL (low-density lipoprotein) cholesteryl esters (CE) from plasma to bile and intestinal perfusates. HDL-CE favored the biliary pathway. Following high-fat feeding, the presence of CETP directed HDL-CE away from the bile and towards the intestine. The presence of CETP increased LDL-CE delivery to bile, whereas the appearance of LDL-CE in intestinal perfusate was near the lower limit of detection. Conclusions: Biliary and intestinal cholesterol secretion can be simultaneously measured in mice and used as a model to examine factors that alter cholesterol elimination. Plasma factors, such as CETP, alter the route of cholesterol elimination from the body. Intestinal and biliary cholesterol secretion rates are independent of transhepatic or transintestinal delivery of HDL-CE, whereas LDL-CE was eliminated almost exclusively in the hepatobiliary pathway.
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Zhao, S. P., A. H. Smelt, A. M. Van den Maagdenberg, A. Van Tol, T. F. Vroom, J. A. Gevers Leuven, A. Van der Laarse, and F. M. Van 't Hooft. "Plasma lipoprotein profiles of normocholesterolemic and hypercholesterolemic homozygotes for apolipoprotein E2(Arg158-->Cys) compared." Clinical Chemistry 40, no. 8 (August 1, 1994): 1559–66. http://dx.doi.org/10.1093/clinchem/40.8.1559.
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Abstract We compared plasma lipoprotein profiles of 15 individuals with normocholesterolemic (plasma cholesterol 4.81 +/- 0.90 mmol/L) familial dysbetalipoproteinemia (NFD) and 15 patients with hypercholesterolemic (plasma cholesterol 10.61 +/- 2.32 mmol/L) familial dysbetalipoproteinemia (HFD), matched for age and sex. All subjects were homozygous for apoE2(Arg158-->Cys). Compared with 15 normolipidemic controls (plasma cholesterol 5.47 +/- 0.92 mmol/L), subjects with NFD and HFD had greater cholesterol concentrations of large very-low-density lipoprotein (VLDL1), small VLDL (VLDL2), and intermediate-density lipoprotein, each of which was correlated to their plasma total cholesterol concentration. VLDL1 and VLDL2 subfractions were enriched in cholesteryl ester, and plasma cholesteryl ester transfer protein activities were increased in both NFD and HFD; however, absolute changes were larger in HFD than in NFD. Concentrations of low-density lipoprotein cholesterol were lower in HFD (1.89 +/- 0.48 mmol/L) and NFD (1.56 +/- 0.36 mmol/L) than in normolipidemic controls (3.35 +/- 0.73 mmol/L). We conclude that all subjects homozygous for apoE2(Arg158-->Cys) show features of dysbetalipoproteinemia.
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Lutton, C. "Dietary cholesterol, membrane cholesterol and cholesterol synthesis." Biochimie 73, no. 10 (October 1991): 1327–34. http://dx.doi.org/10.1016/0300-9084(91)90097-k.
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Napolitano, Mariarosaria, Ida Blotta, Anna Montali, and Elena Bravo. "17β-Estradiol Enhances the Flux of Cholesterol Through the Cholesteryl Ester Cycle in Human Macrophages." Bioscience Reports 21, no. 5 (October 1, 2001): 637–52. http://dx.doi.org/10.1023/a:1014721026280.
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Estrogens have been shown to have many positive effects on the function of arterial wall, and recent evidence suggest that 17β-estradiol has a direct action in reducing the accumulation of cholesteryl ester in macrophages. The mechanisms underlying the effects of 17β-estradiol on foam cell formation, however are poorly understood. The aim of this study is to investigate the role of 17β-estradiol in the regulation of the cholesteryl ester cycle and cholesterol efflux in human macrophages. In addition, the influence of 17β-estradiol on apolipoprotein E (apoE) and lipoprotein lipase (LDL) secretion by the cells was also tested. Human Monocyte Derived Macrophages (HMDM), matured in the presence or the absence of 17β-estradiol, were loaded with [3H]-cholesteryl ester-labeled-acetyl LDL (low density lipoprotein) and the efflux of radioactivity into the medium was measured. The effect of 17β-estradiol on cellular activities of acyl coenzyme A: cholesterol acyl transferase (ACAT), and both neutral and acid cholesteryl ester hydrolase (CEH) and the secretion of apoE and LDL into the medium, were also studied. The results indicate that 17β-estradiol induces an increase in the amount of labeled cholesterol released from the cells and, the data obtained from the measurements of ACAT and CEH activities showed that, in estrogen-treated HMDM, the cholesteryl ester cycle favors the hydrolysis of lipoprotein cholesterol by CEH in comparison with its acylation by ACAT. In particular, for the first time a strong enhancement of neutral and acid CEH in human macrophages by 17β-estradiol, was demonstrated. ApoE and LDL secretion increased during the maturation of monocytes to macrophages, and was not modified by 17β-estradiol. In contrast, loading the cells with cholesterol by incubation in the presence of acetylated or oxidized LDL produced an increase in the levels of apoE secreted by both estrogen-treated and control macrophages. The activity of LPL found in the cell medium, on the other hand, in lipid loaded cells tended to be increased only in estrogen treated macrophages, suggesting that the effects of estrogen on unloaded macrophages are different from those produced on lipid-loaded macrophages. On the whole, the present findings suggest that one of the mechanisms by which 17β-estradiol acts to reduce cholesterol accumulation in macrophages is by increasing reverse cholesterol transport through the enhancement of the cholesteryl ester cycle, so that the generation of intracellular unesterified cholesterol for excretion from the cells is favored.
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Zhao, Bin, Ramesh Natarajan, and Shobha Ghosh. "Human liver cholesteryl ester hydrolase: cloning, molecular characterization, and role in cellular cholesterol homeostasis." Physiological Genomics 23, no. 3 (November 17, 2005): 304–10. http://dx.doi.org/10.1152/physiolgenomics.00187.2005.
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The liver regulates cholesterol homeostasis and eliminates excess cholesterol as bile acids or biliary cholesterol. Free cholesterol for bile acid synthesis or biliary secretion is obtained by the hydrolysis of stored cholesteryl esters or from cholesteryl esters taken up by the liver from high-density lipoproteins via a selective uptake pathway. The present study was undertaken to characterize the enzyme catalyzing this reaction, namely, cholesterol ester hydrolase (CEH) from the human liver, and demonstrate its role in regulating bile acid synthesis. Two cDNAs were isolated from the human liver that differed only in the presence of an additional alanine at position 18 in one of the clones. Transient transfection of COS-7 cells with a eukaryotic expression vector containing either of these two cDNAs resulted in significant increase in the hydrolysis of cholesteryl esters, authenticating these clones as human liver CEH. CEH mRNA and protein expression in human hepatocytes were demonstrated by real-time PCR and Western blot analyses, respectively, confirming the location of this enzyme in the cell type involved in hepatic cholesterol homeostasis. Overexpression of these CEH clones in human hepatocytes resulted in significant increase in bile acid synthesis, demonstrating a role for liver CEH in modulating bile acid synthesis. This CEH gene mapped on human chromosome 16, and the two clones represent two different transcript variants resulting from splice shifts at exon 1. In conclusion, these data identify that human liver CEH was expressed in hepatocytes, where it potentially regulates the synthesis of bile acids and thus the removal of cholesterol from the body.
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Despres, J. P., B. S. Fong, J. Jimenez, P. Julien, and A. Angel. "Selective uptake of HDL cholesterol ester by human fat cells." American Journal of Physiology-Endocrinology and Metabolism 254, no. 5 (May 1, 1988): E667—E675. http://dx.doi.org/10.1152/ajpendo.1988.254.5.e667.
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In humans, high-density lipoprotein (HDL)-cholesterol ester turnover exceeds that of HDL apoproteins by severalfold or more, suggesting an independent catabolic fate of these constituents. The present study investigated the cellular uptake and dissociation of HDL labeled in its apoproteins with 125I and in its cholesterol ester with [3H]cholesteryl palmityl ether, a nonhydrolyzable cholesterol ester analogue. Approximately 50% of cell-associated 125I-HDL2 and 125I-HDL3 was released from prelabeled adipose cells by incubating the latter in the presence or absence of unlabeled lipoproteins for 2 h. The uptake of HDL-cholesterol ester by human fat cells as reflected by [3H]cholesteryl palmityl ether was 5-18 times greater than that predicted from the uptake of 125I-HDL2 and 125I-HDL3 and was irreversible. Analysis of dissociated 125I-HDL3 demonstrated changes to both higher and lower density fractions compared with the starting material. There was a high correlation between the cellular uptake of HDL3-cholesterol ester and HDL3-apoprotein uptakes (r = 0.90, P less than 0.01), suggesting that HDL-cholesterol ester uptake requires a specific apoprotein interaction or binding step. The selective uptake and retention of HDL-cholesterol ester by isolated adipocytes implies that human fat tissue may play a role in regulating the lipid composition of plasma HDL.
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Cadigan, K. M., D. M. Spillane, and T. Y. Chang. "Isolation and characterization of Chinese hamster ovary cell mutants defective in intracellular low density lipoprotein-cholesterol trafficking." Journal of Cell Biology 110, no. 2 (February 1, 1990): 295–308. http://dx.doi.org/10.1083/jcb.110.2.295.
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This paper reports the isolation and characterization of Chinese hamster ovary cell mutants defective in low density lipoprotein (LDL)-cholesterol trafficking. The parental cell line was 25-RA, which possesses LDL receptors and various cholesterogenic enzyme activities that are partially resistant to down regulation by exogenous sterols (Chang, T. Y., and J. S. Limanek. 1980. J. Biol. Chem. 255:7787-7795). Because these cells accumulate a large amount of intracellular cholesteryl ester when grown in medium containing 10% fetal calf serum, mutagenized populations of 25-RA cells were grown in the presence of a specific inhibitor of acyl-coenzyme A: cholesterol acyltransferase (ACAT), which depleted their cholesteryl ester stores. Without this cholesterol ester storage, 99% of 25-RA cells die after 5-d growth in cholesterol starvation medium, while the mutant cells, which accumulate free cholesterol intracellularly, survived. In two mutant clones chosen for characterization, activation of cholesteryl ester synthesis by LDL was markedly reduced in the mutant cells compared with 25-RA cells. This lack of activation of cholesterol ester synthesis in the mutant cells could not be explained by defective uptake and/or processing of LDL or by a decreased amount of ACAT, as determined by in vitro enzyme activity. Mutant cells grown in the presence of LDL contain numerous cytosolic particles that stain intensely with the fluorescent compound acridine orange, suggesting that they are acidic. The particles are also stained with filipin, a cholesterol-specific fluorescent dye. Indirect immunofluorescence with a monoclonal antibody specific for a lysosomal/endosomal fraction revealed a staining pattern that colocalized with the filipin signal. The mutant phenotype was recessive. The available evidence indicates that the mutant cells can take up and process LDL normally, but the hydrolyzed cholesterol accumulates in an acidic compartment, probably the lysosomes, where it can not be transported to its normal intracellular destinations.
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Freeman, Dilys J., Christopher J. Packard, James Shepherd, and Dairena Gaffney. "Polymorphisms in the Gene Coding for Cholesteryl Ester Transfer Protein are Related to Plasma High-Density Lipoprotein Cholesterol and Transfer Protein Activity." Clinical Science 79, no. 6 (December 1, 1990): 575–81. http://dx.doi.org/10.1042/cs0790575.
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1. Cholesteryl ester transfer protein activity may have a physiological effect on high-density lipoprotein levels. 2. We examined restriction fragment length polymorphisms associated with the cholesteryl ester transfer protein gene and the apolipoprotein AI gene in a group of 60 unrelated subjects selected from an initial survey of 5000 subjects on the basis of their high-density lipoprotein levels being high or low at the extremes of the distribution. The activities of cholesteryl ester transfer protein and lectithin:cholesterol acyltransferase (phosphatidylcholine-sterol acyltransferase, EC 2.3.1.43) were also determined. Analysis by selection of those with a low high-density lipoprotein cholesterol level (≤ 1.1 for males, ≤ 1.2 for females) gave 32 individuals with 24% B2 alleles. Selection of subjects with a high-density lipoprotein cholesterol level (≥ 2 mmol/l) gave 17 with 62% B2 alleles. 3. The group with low levels of high-density lipoprotein cholesterol had higher activity of cholesteryl ester transfer protein and significantly elevated triacylglycerol levels when compared with the group with high levels of high-density lipoprotein cholesterol. 4. A further significant finding was the correlation of the Msp1 restriction fragment length polymorphism detected by the apolipoprotein AI gene with lecithin:cholesterol acyltransferase activity.
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Geng, Feng, Yaogang Zhong, Huali Su, Etienne Lefai, William Yong, Arnab Chakravarti, and Deliang Guo. "TMET-05. LIPOPHAGY CONTROLS CHOLESTEROL HOMEOSTASIS AND BRAIN TUMOR GROWTH." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v273. http://dx.doi.org/10.1093/neuonc/noad179.1049.
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Abstract Cholesterol is an essential structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol, but with an abundant presence of cholesteryl esters (CEs) in their lipid droplets (LDs). Mechanistically, we found that SREBP-1, a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked GBM cells became quite sensitive to cholesterol deficiency with poor growth. Our study unravels a previously unrecognized SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis, while providing a potential new therapeutic avenue for GBM
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Saito, Kyoko, Yoshitaka Shirasago, Tetsuro Suzuki, Hideki Aizaki, Kentaro Hanada, Takaji Wakita, Masahiro Nishijima, and Masayoshi Fukasawa. "Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus." Journal of Virology 89, no. 4 (December 3, 2014): 2220–32. http://dx.doi.org/10.1128/jvi.03385-14.
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ABSTRACTHepatitis C virus (HCV) exploits host membrane cholesterol and its metabolism for progeny virus production. Here, we examined the impact of targeting cellular squalene synthase (SQS), the first committed enzyme for cholesterol biosynthesis, on HCV production. By using the HCV JFH-1 strain and human hepatoma Huh-7.5.1-derived cells, we found that the SQS inhibitors YM-53601 and zaragozic acid A decreased viral RNA, protein, and progeny production in HCV-infected cells without affecting cell viability. Similarly, small interfering RNA (siRNA)-mediated knockdown of SQS led to significantly reduced HCV production, confirming the enzyme as an antiviral target. A metabolic labeling study demonstrated that YM-53601 suppressed the biosynthesis of cholesterol and cholesteryl esters at antiviral concentrations. Unlike YM-53601, the cholesterol esterification inhibitor Sandoz 58-035 did not exhibit an antiviral effect, suggesting that biosynthesis of cholesterol is more important than that of cholesteryl esters for HCV production. YM-53601 inhibited transient replication of a JFH-1 subgenomic replicon and entry of JFH-1 pseudoparticles, suggesting that at least suppression of viral RNA replication and entry contributes to the antiviral effect of the drug. Collectively, our findings highlight the importance of the cholesterol biosynthetic pathway in HCV production and implicate SQS as a potential target for antiviral strategies against HCV.IMPORTANCEHepatitis C virus (HCV) is known to be closely associated with host cholesterol and its metabolism throughout the viral life cycle. However, the impact of targeting cholesterol biosynthetic enzymes on HCV production is not fully understood. We found that squalene synthase, the first committed enzyme for cholesterol biosynthesis, is important for HCV production, and we propose this enzyme as a potential anti-HCV target. We provide evidence that synthesis of free cholesterol is more important than that of esterified cholesterol for HCV production, highlighting a marked free cholesterol dependency of HCV production. Our findings also offer a new insight into a role of the intracellular cholesterol pool that is coupled to its biosynthesis in the HCV life cycle.
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Romanenko, Victor G., George H. Rothblat, and Irena Levitan. "Sensitivity of Volume-regulated Anion Current to Cholesterol Structural Analogues." Journal of General Physiology 123, no. 1 (December 29, 2003): 77–88. http://dx.doi.org/10.1085/jgp.200308882.
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Depletion of membrane cholesterol and substitution of endogenous cholesterol with its structural analogues was used to analyze the mechanism by which cholesterol regulates volume-regulated anion current (VRAC) in endothelial cells. Depletion of membrane cholesterol enhanced the development of VRAC activated in a swelling-independent way by dialyzing the cells either with GTPγS or with low ionic strength solution. Using MβCD–sterol complexes, 50–80% of endogenous cholesterol was substituted with a specific analogue, as verified by gas-liquid chromatography. The effects of cholesterol depletion were reversed by the substitution of endogenous cholesterol with its chiral analogue, epicholesterol, or with a plant sterol, β-sitosterol, two analogues that mimic the effect of cholesterol on the physical properties of the membrane bilayer. Alternatively, when cholesterol was substituted with coprostanol that has only minimal effect on the membrane physical properties it resulted in VRAC enhancement, similar to cholesterol depletion. In summary, our data show that these channels do not discriminate between the two chiral analogues of cholesterol, as well as between the two cholesterols and β-sitosterol, but discriminate between cholesterol and coprostanol. These observations suggest that endothelial VRAC is regulated by the physical properties of the membrane.
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Molina, M. T., C. M. Vázquez, and V. Ruiz-Gutierrez. "Changes in both acyl-CoA:cholesterol acyltransferase activity and microsomal lipid composition in rat liver induced by distal-small-bowel resection." Biochemical Journal 260, no. 1 (May 15, 1989): 115–19. http://dx.doi.org/10.1042/bj2600115.
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The acyl-CoA:cholesterol acyltransferase (ACAT) activity and lipid composition of hepatic microsomal membrane were investigated 6 weeks after both 50 and 75% distal-small-bowel resection (SBR). A significant decrease in hepatic cholesteryl ester levels was observed after SBR, with a significant increase in the cholesteryl ester content of the livers of 75% SBR compared with the 50% SBR. Hepatic total acylglycerols, free cholesterol and phospholipid levels were not modified after the surgical operation. Microsomal free cholesterol was increased after both 50 and 75% SBR. However, a decrease in both microsomal ACAT activity and cholesteryl ester levels were found in microsomes (microsomal fractions) of resected rats, both changes being higher after 75 than after 50% resection. The total phospholipid content of the microsomes did not change after the surgical operation. The microsomal phospholipid fatty acid composition indicated higher changes after 75 than after 50% SBR. These results demonstrated that, in resected animals: (1) the activity of the enzyme responsible for catalysing cholesterol esterification (ACAT) is decreased, and (2) hepatic microsomal free cholesterol does not appear to influence the activity of ACAT.
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Zhao, Bin, Jingmei Song, and Shobha Ghosh. "Hepatic overexpression of cholesteryl ester hydrolase enhances cholesterol elimination and in vivo reverse cholesterol transport." Journal of Lipid Research 49, no. 10 (July 3, 2008): 2212–17. http://dx.doi.org/10.1194/jlr.m800277-jlr200.
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Kamanna, V. S., S. I. Saied, L. Evans-Hexdall, and M. A. Kirschenbaum. "Cholesterol esterase in preglomerular microvessels from normal and cholesterol-fed rabbits." American Journal of Physiology-Renal Physiology 261, no. 1 (July 1, 1991): F163—F168. http://dx.doi.org/10.1152/ajprenal.1991.261.1.f163.
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Feeding cholesterol to rabbits produces an atherosclerotic model sharing common metabolic features with the disease in humans, including the vascular lipid accumulation. In coronary vascular cells, this lipid accumulation has been associated with decreased prostacyclin (PGI2) biosynthesis and acid cholesterol esterase activity. Unlike the coronary vascular bed, renal microvasculature appears relatively resistant to atherosclerotic injury. This study examined whether renal microvessels from cholesterol-fed rabbits demonstrated similar metabolic changes in coronary vascular cells. Rabbits were fed either a 0% or 2% cholesterol diet for 1 mo. Similar to coronary vascular cells, in renal microvessels from cholesterol-fed rabbits PGI2 biosynthesis decreased and tissue concentrations of cholesterol and cholesteryl esters increased. However, unlike coronary vascular cells, renal microvascular cholesterol esterase activity increased. Light and electron microscopy revealed sporadic lipid deposits in renal microvessels from cholesterol-fed rabbits and no foam cells or occlusive lesions. In vitro addition of prostanoids to normal renal microvessels had no effect on cholesterol esterase activity. It is inviting to speculate that the increased acid cholesterol esterase activity in renal microvessels from cholesterol-fed rabbits protected them from developing extensive microvascular lesions. These biochemical events may explain the relative resistance of human renal microvessels to the development of occlusive atherosclerotic microvascular lesions.