| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Evidence for a regulatory link between hepatic lipase secretion and intra-hepatocyte cholesterol Henderson, A., N. Coldham, et al. (1993), Biochem Soc Trans 21(2): 138S. |
| Evidence for a regulatory role of cholesterol superlattices in the hydrolytic activity of secretory phospholipase A2 in lipid membranes Liu, F. and P. L. Chong (1999), Biochemistry 38(13): 3867-73. Abstract: We have conducted a detailed study of the effect of membrane cholesterol content on the initial hydrolytic activity of Crotalus durissus terrificus venom phospholipase A2 (sPLA2) in large unilamellar vesicles of cholesterol/dimyristoyl-L-alpha-phosphatidylcholine (DMPC) and cholesterol/1-palmitoyl-2-oleoyl-L-alpha-phosphatidylcholine (POPC) at 37 degrees C. The activity was monitored by using the acrylodan-labeled intestinal fatty acid binding protein and HPLC. In contrast to conventional approaches, we have used small cholesterol concentration increments (approximately 0.3-1.0 mol %) over a wide concentration range (e.g., 13-54 mol % cholesterol). In both membrane systems examined, the initial hydrolytic activity of sPLA2 is found to change with cholesterol content in an alternating manner. The activity reaches a local minimum when the membrane cholesterol content is at or near the critical cholesterol mole fractions (e.g., 14.3, 15.4, 20.0, 22.2, 25.0, 33.3, 40.0, and 50.0 mol % cholesterol) predicted for cholesterol regularly distributed in either hexagonal or centered rectangular superlattices. According to the sterol regular distribution model Chong, P. L.-G. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 10069-10073; Liu et al. (1997) Biophys. J. 72, 2243-2254, the extent of lipid superlattices is maximal at the critical cholesterol mole fractions, at which the membrane free volume is minimal. Thus, our present data can be taken to indicate that the initial hydrolytic activity of sPLA2 is governed by the extent of cholesterol superlattice. These data provide the first functional evidence for the formation of cholesterol superlattices in both saturated (e.g., DMPC) and unsaturated (e.g., POPC) liquid-crystalline phospholipid bilayers. The data also illustrate the functional importance of cholesterol superlattice and demonstrate a new type of regulation of sPLA2. Furthermore, upon binding to cholesterol/POPC large unilamellar vesicles, the intrinsic fluorescence intensity of sPLA2 shows an alternating variation with cholesterol content, exhibiting a minimum at the critical cholesterol mole fractions. This result suggests that either the number of sPLA2 bound to lipid vesicles or the conformation of membrane-bound sPLA2 or both vary with the extent of the cholesterol superlattice in the plane of the membrane. |
| Evidence for a short-term stimulatory effect of insulin on cholesterol synthesis in newly insulin-treated diabetic patients Feillet, C., L. H. Monnier, et al. (1994), Metabolism 43(10): 1233-40. Abstract: To gain further insight into the effects of insulin on cholesterol synthesis in humans, 19 newly insulin-treated diabetic patients were studied before any insulin treatment (study day 1) and after a few days of optimized glycemic control with a continuous intravenous insulin infusion (study day 2). The patients were divided into two groups according to their clinical characteristics and laboratory disorders. Groups I and II consisted, respectively, of 10 newly diagnosed type I diabetic patients and nine type II diabetic patients with secondary failure to oral antidiabetic drugs. Cholesterol synthesis was estimated from the determination of serum lathosterol, a metabolic precursor in the cholesterol pathway, and from the serum lathosterol to cholesterol ratio. Serum cholesterol (millimolar, mean +/- SEM) remained unchanged in both groups. After insulin therapy (study day 2), serum lathosterol (micromolar) and the serum lathosterol to cholesterol ratio (molar ratio x 10(3)) were significantly increased as compared with baseline (study day 1). Serum lathosterol levels were as follows: 9.9 +/- 2.0 versus 4.1 +/- 0.4 (P <.02) in group I, and 9.9 +/- 0.8 versus 5.7 +/- 0.7 (P <.005) in group II; serum lathosterol to cholesterol ratios were 2.10 +/- 0.39 versus 0.86 +/- 0.11 (P <.005) in group I, and 1.92 +/- 0.12 versus 0.98 +/- 0.10 (P <.001) in group II. The data indicate that in newly insulin-treated diabetic patients, short-term intensive insulin therapy has a stimulatory effect on cholesterol synthesis and even results in cholesterol overproduction. |
| Evidence for a synergistic effect of calcium channel blockers with lipid-lowering therapy in retarding progression of coronary atherosclerosis in symptomatic patients with normal to moderately raised cholesterol levels. The REGRESS Study Group Jukema, J. W., A. H. Zwinderman, et al. (1996), Arterioscler Thromb Vasc Biol 16(3): 425-30. Abstract: To date, lipid-lowering therapy appears to be the most effective medical intervention to retard progression of coronary atherosclerosis. In spite of promising experimental results, clinical trials completed so far have failed to demonstrate that calcium channel blockers (CCBs) alone influence the evolution of established coronary atherosclerosis. To assess whether the two therapies may have an additive or synergistic beneficial effect on human atherosclerosis, we reviewed in this regard the data of the angiographic Regression Growth Evaluation Statin Study (REGRESS) trial. REGRESS was designed to determine the effect of lipid-lowering therapy with pravastatin in symptomatic patients with normal to moderately raised cholesterol levels. Angiographically, with respect to the minimum obstruction diameter, in the pravastatin group, patients had on average 0.05 mm (95% confidence interval CI: 0.01-0.09) less progression if cotreated with CCBs compared with no CCB treatment, whereas in the placebo (no pravastatin) group, no effect of CCB treatment was observed (interaction test for differential effect of CCB treatment in patients with pravastatin compared with patients receiving placebo: P=.0016). With respect to the mean segment diameter, similar although not significant (P=.33) results were found. With respect to new lesion formation, in the pravastatin group, there were 50% (CI: 25-83) fewer patients with new angiographic lesions if cotreated with CCBs compared with no CCB cotreatment, whereas in the placebo (no pravastatin) group, no significant effect of CCB treatment was observed (interaction test: P=.0026). No beneficial effects of CCB treatment on clinical events were observed. Although the REGRESS trial was not designed to evaluate combination therapy, the results suggest strongly that addition of CCBs to 3-hydroxy-3-methyl-glutaryl-coenzyme reductase inhibitor therapy (pravastatin) acts synergistically in retarding the progression of established coronary atherosclerosis. |
| Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations Laws, A. and G. M. Reaven (1992), J Intern Med 231(1): 25-30. Abstract: Elevated plasma insulin and triglyceride (TG) and decreased high-density-lipoprotein (HDL)-cholesterol concentrations have been shown to be risk factors for coronary heart disease (CHD). It has been suggested that these metabolic abnormalities are all secondary to resistance to insulin-stimulated glucose uptake. To examine this in more detail, we divided 18 non-diabetic, moderately overweight, sedentary men aged 25-50 years into three groups on the basis of their steady-state plasma glucose levels (SSPG): a low group, (n = 7; SSPG less than 8.3 mmol l-1), a middle group, (n = 6; SSPG 8.3-11.1 mmol l-1), and a high group (n = 5; SSPG greater than 11.1 mmol l-1). The high group had significantly higher fasting (P less than 0.05) and post-oral glucose challenge (P less than 0.01) insulin concentrations, higher fasting TG (P less than 0.05) and lower fasting HDL-cholesterol (P less than 0.05) concentrations than the other two groups. However, there were no statistically significant differences between the groups with regard to body mass index, waist-to-hip ratio or physical endurance capacity as determined by maximal oxygen consumption during a treadmill test. The data suggest that insulin resistance has an effect on the modulation of plasma insulin, TG and HDL-cholesterol concentrations, independent of generalized, abdominal or physical endurance capacity. |
| Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol Mason, R. P., W. J. Shoemaker, et al. (1992), Neurobiol Aging 13(3): 413-9. Abstract: Small angle X-ray diffraction analysis of Alzheimer's disease (AD) lipid membranes extracted from cortical gray matter showed significant, reproducible structure changes relative to age-matched control samples. Specifically, there was an average 4 A reduction in the lipid bilayer width and significant changes in the membrane electron density profiles of AD cortical samples. There were no significant structure differences in the membrane bilayers isolated from an unaffected region (cerebellum) of the AD brain. Lipid and protein analysis of 6 AD and 6 age-matched controls showed that the phospholipid:protein mass ratio was unchanged but that the unesterified cholesterol:phospholipid (C:PL) mole ratio decreased by 30% in the AD temporal gyrus relative to age-matched controls. By contrast, the C:PL mole ratio in the cerebellum did not change significantly. X-ray diffraction analysis of a cholesterol enriched AD sample demonstrated a virtual restoration of the normal membrane bilayer width and electron density profile, suggesting that the cholesterol deficit played a major role in the AD lipid membrane structure perturbation. Alterations in the composition and structure of the membrane bilayer may play an important role in the pathophysiology of AD by altering the activity and catabolism of membrane-bound proteins, including the beta-amyloid precursor protein. |
| Evidence for cholesterol scavenging by Pneumocystis and potential modifications of host-synthesized sterols by the P. carinii SAM:SMT Worsham, D. N., M. Basselin, et al. (2003), J Eukaryot Microbiol 50 Suppl: 678-9. |
| Evidence for cytokine regulation of cholesterol metabolism in herpesvirus-infected arterial cells by the lipoxygenase pathway Etingin, O. R. and D. P. Hajjar (1990), J Lipid Res 31(2): 299-305. Abstract: Cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and gamma-interferon (IF) are produced by activated hematopoietic cells. They possess antiviral activity and have other biological activities such as induction of cell proliferation and hemorrhagic necrosis of tumors. Since herpes simplex virus (HSV) infection of human vascular cells is known to produce a biochemical and cytopathological effect virtually indistinguishable from atherosclerosis, we hypothesized that these cytokines many prevent cholesteryl ester (CE) accumulation in arterial smooth muscle cells (SMC) that is seen with herpesvirus infection. We now report that TNF and IL-1 but not gamma-IF prevent CE accumulation in HSV-infected arterial SMC by induction of cyclic AMP-dependent CE hydrolysis. This effect is mediated through the arachidonate 12-lipoxygenase pathway via 12-HETE since pretreatment of cells with several lipoxygenase inhibitors abolishes the antiviral effect and 12-HETE is the major (greater than 99%) lipoxygenase metabolite produced by these cells. This conclusion is further based on our observations that TNF and IL-1 enhance 12-HETE production in SMC and that 12-HETE significantly increases both intracellular cyclic AMP and lysosomal CE hydrolysis. Moreover, dibutyryl cyclic AMP restored a normal phenotype in these virally infected cells. Collectively, these findings identify for the first time a biochemical mechanism involved in the reduction of lipid accumulation in virally infected arterial SMC by these potent cytokines. |
| Evidence for de novo cholesterol synthesis by term human fetal amnion and chorion: a comparative study using the reverse-isotope dilution technique Loganath, A., K. L. Peh, et al. (2000), Horm Res 53(3): 125-8. Abstract: The cholesterol biosynthetic activity was assessed using 2-(14)C-acetate as substrate in the homogenates of amnion and chorion obtained from women (n = 6, age 26-39 years) after spontaneous labour at term (37-40 weeks of gestation) having uncomplicated pregnancies. Reverse-isotope dilution analysis gave positive identification of (14)C-cholesterol acetate in all incubations of viable tissues. This metabolite was not evident in heat-denatured homogenates which served as controls. The extent of enzymic conversion for amnion at 2.6 x 10(-3) to 0.19% was persistently higher than that of the chorion at 1.7 x 10(-3) to 9.0 x 10(-3)%. The results indicate that human term fetal membranes possess the full complement of enzymes to catalyze the transformation of acetate to cholesterol. This study provides evidence that fetal membranes possess the capacity for de novo cholesterol biosynthesis, the sterol being essential for steroidogenesis as well as in embryo viability during pregnancy. |
| Evidence for distinct cholesterol domains in fiber cell membranes from cataractous human lenses Jacob, R. F., R. J. Cenedella, et al. (2001), J Biol Chem 276(17): 13573-8. Abstract: Previous studies in our laboratory have provided direct evidence for the existence of distinct cholesterol domains within the plasma membranes of human ocular lens fiber cells. The fiber cell plasma membrane is unique in that it contains unusually high concentrations of cholesterol, with cholesterol to phospholipid (C/P) mole ratios ranging from 1 to 4. Since membrane cholesterol content is disturbed in the development of cataracts, it was hypothesized that perturbation of cholesterol domain structure occurs in cataracts. In this study, fiber cell plasma membranes were isolated from both normal (control) and cataractous lenses and assayed for cholesterol and phospholipid. Control and cataractous whole lens membranes had C/P mole ratios of 3.1 and 1.7, respectively. Small angle x-ray diffraction approaches were used to directly examine the structural organization of the cataractous lens plasma membrane versus control. Both normal and cataractous oriented membranes yielded meridional diffraction peaks corresponding to a unit cell periodicity of 34.0 A, consistent with the presence of immiscible cholesterol domains. However, comparison of diffraction patterns indicated that cataractous lens membranes contained more pronounced and better defined cholesterol domains than controls, over a broad range of temperature (5-40 degrees C) and relative humidity (52-92%) levels. In addition, diffraction analyses of the sterol-poor regions of cataractous membranes indicated increased membrane rigidity as compared with control membranes. Modification of the membrane lipid environment, such as by oxidative insult, is believed to be one potential mechanism for the formation of highly resolved cholesterol domains despite significantly reduced cholesterol content. The results of this x-ray diffraction study provide evidence for fundamental changes in the lens fiber cell plasma membrane structure in cataracts, including the presence of more prominent and highly ordered, immiscible cholesterol domains. |
| Evidence for diurnal periodicity in human cholesterol synthesis Jones, P. J. and D. A. Schoeller (1990), J Lipid Res 31(4): 667-73. Abstract: Diurnal variation in human cholesterol synthesis in the rapidly exchangeable pool was studied in six healthy normolipidemic individuals by measurement of deuterium incorporation from body water into plasma cholesterol. After oral administration of D2O, free and de-esterified plasma cholesterol and plasma water were sampled over 48 h, converted to hydrogen, and deuterium enrichment was determined by isotope ratio mass spectrometry. Deuterium enrichment changes over 4-h intervals were used to calculate fractional synthetic rate (FSR). No significant time effects were observed on plasma total cholesterol levels over the 48-h study. The highest rate of deuterium incorporation into free cholesterol occurred during early morning, whereas during afternoon and early evening incorporation rates were lower. Free cholesterol FSR values were lowest at 14:00 to 18:00 h and peaked at 06:00 h. The periodicity across timepoints was not significantly different from that of a derived sine function equation. For cholesteryl ester, FSR data showed less distinct variation over time, peaking during early morning, indicative of maximal efflux of free cholesterol to the ester pool during this period. These findings offer direct evidence for diurnal patterns in human cholesterol synthesis. |
| Evidence for extralysosomal hydrolysis of high-density lipoprotein cholesteryl esters in rat hepatoma cells (Fu5AH): a model for delivery of high-density lipoprotein cholesterol DeLamatre, J. G., R. M. Carter, et al. (1991), J Cell Physiol 146(1): 18-24. Abstract: Rat hepatoma cells (Fu5AH) were studied as a model for the net delivery of apoE-free high-density lipoprotein (HDL) cholesterol to a cell. Incubating cells with HDL results in 1) a decrease in both media-free cholesterol and cholesteryl ester concentration; 2) decreased cell sterol synthesis; and 3) increased cell cholesteryl ester synthesis. HDL cholesteryl ester uptake is increased when cells are incubated for 18 hr in cholesterol poor media. Coincubation of 3H-cholesteryl ester-labeled low-density lipoprotein (LDL) with 50 microM chloroquine or 25 microM monensin results in a decrease in the cellular free cholesterol/cholesteryl ester (FC/CE) isotope ratio, indicating an inhibition in the conversion of cholesteryl ester to free cholesterol. In contrast, chloroquine and monensin do not alter the cellular FC/CE isotope ratio for 3H-CE HDL. This evidence indicates that acidic lysosomal cholesteryl ester hydrolase does not account for the hydrolysis of HDL-CE. Free cholesterol generated from 3H-cholesteryl ester of both LDL and HDL is reesterified intracellularly. At higher HDL concentrations (above 50 micrograms/ml) HDL cholesteryl ester hydrolysis is sensitive to chloroquine. We propose that an extralysosomal pathway is operating in the metabolism of HDL cholesterol and that at higher HDL concentrations a lysosomal pathway may be functioning in addition to an extralysosomal pathway. |
| Evidence for generation of a large amount of nitric oxide-like vascular smooth muscle relaxant by cholesterol-rich neutrophils Mehta, J. L., D. L. Lawson, et al. (1990), Biochem Biophys Res Commun 173(1): 438-42. Abstract: To determine the effect of cholesterol incorporation on the ability of neutrophils to generate superoxide radicals and nitric oxide-like vasorelaxant material, isolated human neutrophils were incubated with cholesterol-rich liposomes, which increased total cholesterol content by 141% and esterified cholesterol content by 523%. Cholesterol loading resulted in 5 to 7 fold increase in cytosolic calcium in resting as well as in PMA or f-MLP-stimulated cells, but a marked (P less than 0.01) reduction in both PMA- and f-MLP-stimulated superoxide radical generation by these cells. Nitric oxide-like activity measured as relaxation of rat aortic rings was more pronounced (P less than 0.02) in cholesterol-rich than in cholesterol-poor cells. The greater relaxation of aortic rings in response to cholesterol-rich neutrophils was observed in rings with or without intact endothelium, and was potentiated by superoxide dismutase and inhibited by oxyhemoglobin as well as L-NMMA, thus suggesting that the vasorelaxant material was nitric oxide. The greater generation of nitric oxide by cholesterol-rich neutrophils occurs perhaps in response to increased cytosolic calcium. |
| Evidence for genetic factors explaining the association between birth weight and low-density lipoprotein cholesterol and possible intrauterine factors influencing the association between birth weight and high-density lipoprotein cholesterol: analysis in twins RG, I. J., C. D. Stehouwer, et al. (2001), J Clin Endocrinol Metab 86(11): 5479-84. Abstract: Recent studies have demonstrated an association between low weight at birth and an atherogenic lipid profile in later life. To examine the influences of intrauterine and genetic factors, we investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. Regression analysis demonstrated that low birth weight was associated with high levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (-0.17 mmol/liter per kg, P = 0.07; -0.18 mmol/liter per kg, P = 0.04; and -0.07 g/liter per kg, P = 0.02, respectively) and with low levels of high-density lipoprotein (HDL) cholesterol (+0.04 mmol/liter per kg, P = 0.1), after adjustment for age, sex, and body mass index. Intrapair differences in birth weight were significantly associated with differences in total cholesterol, LDL cholesterol, and apolipoprotein B in dizygotic twins after adjustment for differences in current body mass index (-0.49 mmol/liter per kg, P = 0.02; -0.51 mmol/liter per kg, P = 0.01; and -0.10 g/liter per kg, P = 0.04, respectively), demonstrating that the larger the difference in birth weight, the higher these risk factors in the twin with the lower birth weight, compared with the cotwin with the higher birth weight. In monozygotic twins, however, the associations between intrapair differences in birth weight and differences in total cholesterol, LDL cholesterol, and apolipoprotein B were in the opposite direction (+0.32 mmol/liter per kg, P = 0.03; +0.23 mmol/liter per kg, P = 0.08; and +0.06 g/liter per kg, P = 0.04, respectively). The association between intrapair differences in birth weight and differences in HDL cholesterol was not significant in dizygotic twins (+0.04 mmol/liter per kg, P = 0.6) and of borderline significance in monozygotic twins (+0.11 mmol/liter per kg, P = 0.05). These data suggest that genetic factors account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association between birth weight and HDL cholesterol. |
| Evidence for impaired cellular cholesterol removal mediated by apo A-I containing lipoproteins in patients with familial lecithin: cholesterol acyltransferase deficiency Ohta, T., R. Nakamura, et al. (1994), Biochim Biophys Acta 1213(3): 295-301. Abstract: We investigated the cholesterol reducing capacity of two species of lipoproteins containing apo A-I, one containing only apo A-I (LpA-I) and the other containing apo A-I and apo A-II (LpA-I/A-II), in 7 patients (4 homozygotes and 3 heterozygotes) with familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Interaction of normal LpA-I or LpA-I/A-II with macrophage foam cells induced a mass reduction in cholesterol from these cells and the cholesterol reducing capacity of LpA-I was greater than that of LpA-I/A-II. When foam cells were incubated with these lipoproteins from homozygotes or heterozygotes, the capacity of LpA-I and LpA-I/A-II particles to reduce cellular cholesterol was decreased by approx. 50% in the homozygotes but was increased by 25-50% in the heterozygotes. These results suggest that LpA-I and LpA-I/A-II isolated from homozygotes and from heterozygotes differ in their ability to accept cellular cholesterol. The former are poor and the latter good acceptors of intracellular cholesterol. We conclude that factors other than reverse cholesterol transport via apo A-I containing lipoproteins have to be considered to explain why homozygotes for LCAT deficiency are not at high risk for premature atherosclerosis. |
| Evidence for induction of nonendothelial NO synthase in aortas of cholesterol-fed rabbits Verbeuren, T. J., E. Bonhomme, et al. (1993), J Cardiovasc Pharmacol 21(5): 841-5. Abstract: The aim of our study was to examine the effects of the inhibitor of nitric oxide (NO)-synthase, nitro-L-arginine (L-NNA), in atherosclerotic aortas obtained from cholesterol-fed rabbits. In the atherosclerotic aortas, L-NNA (100 microM) caused endothelium-independent contractions that were not observed in aortas from control rabbits. L-NNA (100 microM) significantly enhanced the contractile responses to norepinephrine and 5-hydroxytryptamine (5-HT) in atherosclerotic aortas with and without endothelium; in control aortas, L-NNA only augmented the response to 5-HT when the endothelium was present. The concentration-dependent increases in the norepinephrine-induced contractions caused by L-NNA (1 to 100 microM) could be reversed by L-arginine (1 mM) both in atherosclerotic aortas with and without endothelium. L-NMMA also evoked concentration-dependent augmentations of the norepinephrine-induced contraction; the effect of L-NMMA was equipotent to that of L-NNA. Finally, L-NNA (100 microM) prevented the paradoxical endothelium-independent contraction to hypoxia in atherosclerotic aortas. These data strongly suggest that nonendothelial NO synthase has been induced in the aortas of the hyperlipidemic rabbit. |
| Evidence for inhibition of low density lipoprotein oxidation and cholesterol accumulation by apolipoprotein H (beta2-glycoprotein I) Lin, K. Y., J. P. Pan, et al. (2001), Life Sci 69(6): 707-19. Abstract: Low density lipoprotein (LDL) oxidation and lipid accumulation are thought to enhance the progression of atherosclerosis. Apolipoprotein H (apoH) has been implicated in the development of human atherosclerosis. However, the roles of apoH in the oxidative modification of LDL and cellular accumulation of lipid constituents remained uncharacterized. In this study, the level of plasma apoH was found to be significantly associated with the oxidative susceptibility of LDL in human subjects. Plasma levels of apoH were positively correlated with the lag time but negatively correlated with LDL oxidation rate in conjugated diene formation. By using a J774 A.1 macrophage culture system, we found that apoH could not only inhibit the formation of conjugated diene and thiobarbituric acid-reactive substances, but also reduce the electrophoretic mobility of oxidized LDL. Furthermore, apoH decreased cellular accumulation of cholesterol via a reduction in cholesterol influx and an increase in cholesterol efflux. This is the first demonstration that apoH appears to have "antioxidant"-like effects on LDL oxidation. The results also suggest that apoH can inhibit the translocation of cholesterol from extracellular pools to macrophages, suggesting that apoH may play an important role in the prevention of atherosclerosis. |
| Evidence for maximal treatment of atherosclerosis: drastic reduction of cholesterol and fibrinogen restores vascular homeostasis Jaeger, B. R. (2001), Ther Apher 5(3): 207-11. Abstract: This article summarizes the clinical and biochemical evidence for maximal treatment of atherosclerosis by a simultaneous 60% to 70% reduction of plasma low-density lipoprotein cholesterol (LDL cholesterol), fibrinogen, and lipoprotein a concentrations with heparin-mediated extracorporeal LDL/fibrinogen precipitation (HELP) apheresis and statins. Apheresis has proven efficient and safe in the treatment of more than 1,000 patients since 1984 and has been applied in children and adults for the treatment of homozygous and heterozygous familial hypercholesterolemia, coronary artery disease, ischemic cardiomyopathy, generalized atherosclerosis, or transplant-associated arteriosclerosis after cardiac transplantation. Simultaneous removal of the main atherogenic plasma compounds has an immediate impact on myocardial and peripheral vasomotion by increasing myocardial blood flow, coronary flow reserve, cerebral CO2-reactivity, and muscle oxygen tension. Removal of fibrinogen and cholesterol reduces plasma viscosity by 20% and erythrocyte aggregation by 60% which gives rise to applying the HELP apheresis in various microcirculatory disorders. Pilot studies on acute retinal ischemia, critical limb ischemia, and sudden hearing loss confirm this observation. |
| Evidence for multiple complementary pathways for efficient cholesterol absorption in mice Iqbal, J. and M. M. Hussain (2005), J Lipid Res 46(7): 1491-501. Abstract: Apolipoprotein B (apoB)-dependent and apoB-independent pathways for cholesterol transport have been described in cultured cells. Here, we show that the apoB-independent pathway involves apoA-I-containing high density lipoproteins (HDLs). Cholesterol secretion by the HDLs, but not by the apoB pathway, was significantly reduced in primary enterocytes isolated from chow- and cholesterol-fed apoA-I(-/-) mice. These enterocytes were capable of cholesterol efflux when apoA-I was provided extracellularly. In apoA-I(-/-) mice, the absorption of a bolus of cholesterol was similar in control and apoA-I(-/-) mice fed chow or high-cholesterol diet. However, short-term studies revealed that cholesterol absorption was occurring over longer lengths of the intestine, and cholesterol but not triglyceride transport to the plasma and liver in chow- and cholesterol-fed apoA-I(-/-) mice was significantly reduced. These studies indicate that in apoA-I deficiency, there is a delay in cholesterol absorption, but cholesterol is eventually absorbed because of the compensatory apoB pathway. Nonetheless, long-term studies involving multiple feedings showed significant reduction in cholesterol absorption after 4 days. We propose that multiple compensatory mechanisms ensure efficient cholesterol absorption in mice. |
| Evidence for reverse cholesterol transport in vivo from liver endothelial cells to parenchymal cells and bile by high-density lipoprotein Bakkeren, H. F., F. Kuipers, et al. (1990), Biochem J 268(3): 685-91. Abstract: Acetylated low-density lipoprotein (acetyl-LDL), biologically labelled in the cholesterol moiety of cholesteryl oleate, was injected into control and oestrogen-treated rats. The serum clearance, the distribution among the various lipoproteins, the hepatic localization and the biliary secretion of the 3Hcholesterol moiety were determined at various times after injection. In order to monitor the intrahepatic metabolism of the cholesterol esters of acetyl-LDL in vivo, the liver was subdivided into parenchymal, endothelial and Kupffer cells by a low-temperature cell-isolation procedure. In both control and oestrogen-treated rats, acetyl-LDL is rapidly cleared from the circulation, mainly by the liver endothelial cells. Subsequently, the cholesterol esters are hydrolysed, and within 1 h after injection, about 60% of the cell- associated cholesterol is released. The 3Hcholesterol is mainly recovered in the high-density lipoprotein (HDL) range of the serum of control rats, while low levels of radioactivity are detected in serum of oestrogen-treated rats. In control rats cholesterol is transported from endothelial cells to parenchymal cells (reverse cholesterol transport), where it is converted into bile acids and secreted into bile. The data thus provide evidence that HDL can serve as acceptors for cholesterol from endothelial cells in vivo, whereby efficient delivery to the parenchymal cells and bile is assured. In oestrogen-treated rats the radioactivity from the endothelial cells is released with similar kinetics as in control rats. However, only a small percentage of radioactivity is found in the HDL fraction and an increased uptake of radioactivity in Kupffer cells is observed. The secretion of radioactivity into bile is greatly delayed in oestrogen-treated rats. It is concluded that, in the absence of extracellular lipoproteins, endothelial cells can still release cholesterol, although for efficient transport to liver parenchymal cells and bile, HDL is indispensable. |