| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Impaired cholesterol esterification in the plasma in patients with breast cancer Subbaiah, P. V., M. Liu, et al. (1997), Lipids 32(2): 157-62. Abstract: An important factor which determines the movement of cholesterol in and out of the cells is the free cholesterol (FC)/esterified cholesterol (EC) ratio in the plasma. Although this ratio has been shown to be increased in several types of malignancies in humans as well as experimental animals, it is not known whether such an abnormality is found in breast cancer patients. Furthermore, the reasons for such an increase in cancer patients are unknown. We studied the plasma lipid composition and the activity of lecithin-cholesterol acyltransferase (LCAT), the enzyme responsible for the formation of most of EC in human plasma, in 12 women with breast cancer and 9 age-matched control women. The plasma EC concentration was found to be significantly decreased in cancer patients, whereas the FC concentration was unchanged, leading to increased FC/EC ratios (P < 0.05). The concentration of phosphatidylcholine, the acyl donor in the LCAT reaction, was decreased significantly, whereas all other phospholipids were unaffected. The cholesterol-esterifying activity of LCAT was significantly lower in cancer patients, whether assayed with endogenous substrates (P < 0.05), or with an exogenous substrate (P < 0.01). However, another function of the enzyme, namely the lysolecithin acyltransferase activity, was increased (P < 0.02), indicating that the enzyme concentration in plasma may not be decreased. These results show that the increase in the FC/EC ratio in cancer patients is due to an impaired esterification of cholesterol by plasma LCAT, probably due to an alteration in the composition of substrate lipoproteins, or the presence of an inhibitory factor. |
| Impaired cholesterol synthesis rate in fibroblasts and reduced cellular uptake of LDLs derived from peroxisome-deficient patients cause cellular cholesterol deficiency in peroxisome-deficient fibroblasts Mandel, H., M. Getsis, et al. (1996), Ann N Y Acad Sci 804: 752-5. |
| Impaired cytoprotective function of muscle in human gallbladders with cholesterol stones Xiao, Z. L., J. Amaral, et al. (2005), Am J Physiol Gastrointest Liver Physiol 288(3): G525-32. Abstract: Acute cholecystitis develops in gallbladders (GB) with excessive bile cholesterol (Ch). Increased membrane Ch content affects membrane function and may affect PGE(2) receptors involved in the cytoprotection against acute inflammation. This study was aimed at determining whether the cytoprotective response to PGE(2) is affected by lithogenic bile with Ch. Muscle cells from human GB with cholesterol stones (ChS) or pigment stones (PS) were obtained by enzymatic digestion. PGE(2) levels were measured by radioimmunoassay, and activities of superoxide dismutase (SOD) and catalase were assayed by spectrophotometry. The contraction in response to H(2)O(2) in muscle cells from PS was 14 +/- 0.3%, not different from normal controls, and decreased after the cells were incubated with Ch-rich liposomes (P < 0.05), which increase the Ch content in the plasma membranes. In muscle cells from GB with ChS, H(2)O(2)-induced contraction was only 9.2 +/- 1.3% and increased to 14 +/- 0.2% after Ch-free liposome treatment to remove Ch from the plasma membranes (P < 0.01). H(2)O(2) caused a similar increase in the levels of lipid peroxidation and PGE(2) content in muscle cells from GBs with ChS and PS. However, the activities of SOD and catalase were significantly lower in muscle cells from GBs with ChS compared with those with PS. The binding capacity of PGE(2) receptors was also significantly lower in muscle cells from GBs with ChS compared with those with PS. In conclusion, the cytoprotective response to reactive oxygen species is reduced in muscle cells from GBs with ChS despite a normal increase in the cellular levels of PGE(2). This impaired cytoprotective response may be due to a dysfunction of PGE(2) receptors with decreased binding capacity resulting from excessive Ch levels in the plasma membrane. |
| Impaired function of lecithin:cholesterol acyltransferase in atherosclerosis-susceptible White Carneau pigeons: possible effects on metabolism of oxidized phospholipids Liu, M., R. W. St Clair, et al. (1998), J Lipid Res 39(2): 245-54. Abstract: Although White Carneau (WC) pigeons are known to be more susceptible to atherosclerosis than Show Racer (SR) pigeons, the reasons for this difference are not fully understood. While no major differences are known in the lipoprotein composition, a difference in the cholesteryl ester (CE) composition was reported. However, there is little information on the activity or specificity of lecithin:cholesterol acyltransferase (LCAT), the major source of plasma CE. In order to determine whether the esterification of cholesterol or other functions of LCAT are compromised in WC pigeons, we studied the various reactions catalyzed by LCAT in the two groups. The cholesterol esterification was found to be significantly lower in WC pigeons, whether assayed with exogenous or endogenous substrates. Furthermore, lyso phosphatidylcholine (PC) esterification and oxidized PC hydrolysis, two other reactions carried out by LCAT, were also lower in WC. We found evidence for the presence of an active lysophospholipase in pigeon plasma, and this activity was also lower in WC compared to SR. A significant increase in the FC/PC ratio, another reported atherogenic risk factor, was found in WC. plasma. Because of the absence of other hydrolytic enzymes in pigeon plasma, LCAT may play an important role in the metabolism of oxidized PC generated during lipoprotein oxidation, and therefore a decrease in its activity in White Carneau pigeons may contribute to increased risk of atherosclerosis. |
| Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile Corradini, S. G., W. Elisei, et al. (2000), Gastroenterology 118(5): 912-20. Abstract: BACKGROUND & AIMS: The role of the gallbladder in gallstone pathogenesis is still unclear. We examined the effects of gallbladder mucosal lipid absorption on lipid composition and cholesterol crystallization in bile. METHODS: The in vitro-isolated, intra-arterially perfused gallbladder model was used (1) to compare the absorption rates of lipids from standard bile by gallbladders obtained from 7 patients with cholesterol gallstones and 6 controls; and (2) to measure the microscopic cholesterol crystal detection time in cholesterol-enriched pig bile before and after lipid absorption by the pig gallbladder. RESULTS: Control gallbladders, but not cholesterol gallstone gallbladders, significantly reduced cholesterol (P < 0.02) and phospholipid (P < 0.01) and increased bile salt (P < 0.01) molar percentages in bile over a 5-hour period by efficient and selective cholesterol and phospholipid absorption. A histomorphometric study of the epithelial cells showed significantly higher values for nuclear density (P < 0.01) and nuclear (P < 0.05) and cytoplasmic (P < 0.05) areas in the cholesterol gallstone than the control group. Sequential microscopy of cholesterol-enriched pig bile showed significantly shorter cholesterol filament (P < 0.01) and typical cholesterol plate (P < 0. 02) detection times before than after exposure of bile to the gallbladder lipid absorption. CONCLUSIONS: In cholesterol gallstone disease, the human gallbladder epithelium loses its capacity to selectively and efficiently absorb cholesterol and phospholipids from bile, even if it is hyperplastic and hypertrophic. This epithelial dysfunction eliminates the positive effect that the normal gallbladder exerts on cholesterol solubility in bile and might be a pathogenetic cofactor for cholesterol gallstone formation. |
| Impaired mobilisation of cholesterol from stored cholesteryl esters in human (THP-1) macrophages Graham, A., A. D. Angell, et al. (1996), Atherosclerosis 120(1-2): 135-45. Abstract: The formation of macrophage-derived foam cells is central to the development of fatty streaks within the arterial wall, and to the progression of atherosclerosis. The unregulated deposition of cholesteryl esters, as lipid droplets within the cytoplasm of these cells, is responsible for the formation of foam cells; this process is thought to be regulated by the balance between cholesterol esterification, by acyl CoA:cholesterol acyltransferase (ACAT), and hydrolysis, by neutral cholesteryl ester hydrolase (nCEH). This study examines the importance of the balance between these two enzymes in determining the efflux of cholesterol from human (THP-1) macrophages. The presence of modified lipoprotein, or of 25-hydroxycholesterol, markedly increased cholesterol esterification in these cells and these effects were potently inhibited by the presence of the ACAT inhibitor, 447C88. In the absence of HDL, an acceptor particle, there was little or no hydrolysis of the cholesteryl ester pool and no efflux of cholesterol to the extracellular milieu; addition of HDL led to a partial (36%) reduction in cholesteryl esters, an effect which was not enhanced by the inhibition of ACAT. This suggested that the stored cholesteryl esters in human (THP-1) macrophages, unlike those in mouse peritoneal macrophages, were relatively resistant to removal by efflux to HDL. Efflux of newly synthesised free cholesterol from these macrophages was increased by HDL in a saturable manner, suggesting that the lack of reduction of stored cholesteryl esters was due to impaired mobilisation of cholesteryl esters to free cholesterol via nCEH. Indeed, nCEH activity in these macrophages was much lower than in mouse peritoneal macrophages, and appeared to be down-regulated in the presence of 25-hydroxycholesterol or modified lipoproteins; this loss of nCEH activity was prevented by the ACAT inhibitor 447C88. The efflux of stored cholesteryl esters from THP-1 macrophages therefore appears to be limited by the activity of nCEH. |
| Impaired plasma viscosity via increased cholesterol levels in peripheral occlusive arterial disease correction of disase Ercan, M., C. Koksal, et al. (2003), Clin Hemorheol Microcirc 29(1): 3-9. Abstract: The aim of this study was to investigate the relationship between plasma viscosity and lipoprotein and apolipoprotein pattern in normo- and hypercholesterolemic patients with peripheral occlusive arterial disease (POAD). 40 patients with POAD have been selected (8 females and 32 males, mean age: 54+/-3.2 years) with clinically evident superficial femoral occlusive artery disease. They were separated into two groups as normocholesterolemic (plasma total cholesterol <200 mg/dl) and hypercholesterolemic (plasma total cholesterol >200 mg/dl). Plasma total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, total protein, and albumin levels were determined by enzymatic methods using commercial kits. Levels of apolipoprotein AI (apo AI), and apolipoprotein B (apo B) were measured using a immunoturbidometric method. Plasma viscosity (PV) was measured by capillary viscometer. Classifying the patients with PAOD according to the cholesterol levels; hypercholesterolemic (mean total-cholesterol: 227.90+/-26.97 mg/dl) patients had significantly higher LDL-C, PV and triglyceride levels compared with nornocholesterolemic patients (p<0.001, p<0.001, p<0.001, respectively). HDL-C and apo B were significantly lower in hypercholesterolemic patients than in normocholesterolemic patients (p<0.001, p<0.001, respectively). PV was positively correlated with total cholesterol (r=0.485, p<0.05), atherogenic index (r=0.624, p<0.01), total-C/HDL-C ratio (r=0.624, p<0.05), and LDL-C/HDL-C ratio (r=0.707, p<0.001) in hypercholesterolemic patients with POAD. PV was higher in hypercholesterolemic patients with POAD than in normocholesterolemic patients with POAD. We suggest that POAD patients should be regarded as a heterogenous group with lipid and lipoprotein parameters in order to assess the microcirculation in the affected limb. In case of dyslipidemia in POAD patients an elevated plasma viscosity should be considered as coexisting risk factor. |
| Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation Heeren, J., T. Grewal, et al. (2004), J Biol Chem 279(53): 55483-92. Abstract: After internalization of triglyceride-rich lipoproteins (TRL) in hepatoma cells, TRL particles are immediately disintegrated in the early endosomal compartment. This involves the targeting of lipids and apoprotein B along the degradative pathway and the recycling of TRL-derived apoE through recycling endosomes. Re-secretion of apoE is accompanied by the concomitant association of apoE and cellular cholesterol with high-density lipoproteins (HDL). Since epidemiological data showed that apoE3 and apoE4 have differential effects on HDL metabolism, we investigated whether the intracellular processing of TRL-derived apoE4 differs from apoE3-TRL. In this study, we demonstrated by radioactive and immunofluorescence uptake experiments that cell-surface binding and internalization of TRL-derived apoE4 are increased compared with apoE3 in hepatoma cells. Pulse-chase experiments revealed that HDL-induced recycling, but not disintegration and degradation, of apoE4-enriched TRL is strongly reduced in these cells. Furthermore, impaired HDL-induced apoE4 recycling is associated with reduced cholesterol efflux. Studies performed in Tangier fibroblasts showed that apoE recycling does not depend on ATP-binding cassette transporter A1 activity. These studies provide initial evidence that impaired recycling of apoE4 could interfere with intracellular cholesterol transport and contribute to the pathophysiological lipoprotein profile observed in apoE4 homozygotes. |
| Impaired regulation of sterol regulatory element binding protein 2 in cholesterol gallstone-susceptible mice Xu, G., O. Muller, et al. (2004), Biochim Biophys Acta 1688(3): 274-9. Abstract: Lipid synthesis is under tight transcriptional control involving sterol regulatory element binding proteins (SREBP1, SREBP2). Rising cellular cholesterol levels prevent SREBP2 from entering the nucleus to directly activate the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), the key enzyme of cholesterol synthesis. The failure to down-regulate cholesterol synthesis in gallstone-susceptible C57L/J but not AKR/J mice prompted us to study the processing of SREBP2 in these mice. Male mice of each strain received a control or lithogenic diet for 28 days. Membrane and nuclear extracts of pooled livers were prepared for immunoblot analysis of SREBP. Steady-state mRNA levels of Hmgcr, Srebp1, Srebp2 and the SREBP cleavage activating protein (Scap) were measured from individual livers. There was no marked difference between the two strains with regard to processing of SREBP1 as well as steady-state mRNA levels of Srebp1, Srebp2 and Scap. However, a near-complete suppression of nuclear SREBP2 related to low Hmgcr mRNA levels was noticed only for gallstone-resistant AKR mice. Abnormal regulation of SREBP2 appears to be responsible for the failure to suppress cholesterol synthesis in genetically cholesterol gallstone-susceptible mice. This defect may contribute to cholesterol hypersecretion and gallstone formation. |
| Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels Clarkson, P., D. S. Celermajer, et al. (1996), J Am Coll Cardiol 28(3): 573-9. Abstract: OBJECTIVES: This study sought to examine whether endothelial function is impaired in the large vessels of asymptomatic young adults with insulin-dependent diabetes and whether endothelial dysfunction is related to duration or control of diabetes, small-vessel disease or other vascular risk factors. BACKGROUND: Endothelial dysfunction is an early event in atherosclerosis, and large-vessel atherosclerotic disease is the major cause of morbidity and mortality in diabetes. METHODS: We compared 80 young adults with insulin-dependent diabetes (15 to 40 years old; mean +/- SD diabetes duration 13 +/- 8 years) with 80 matched nondiabetic control subjects. Using high resolution vascular ultrasound, we measured brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilation) and sublingual glyceryltrinitrate (causing endothelium-independent dilation). RESULTS: Flow-mediated dilation was significantly impaired in diabetic subjects (5.0 +/- 3.7% vs. 9.3 +/- 3.8% in control subjects, p < 0.001). The ratio of flow-mediated dilation to glyceryltrinitrate-induced dilation was significantly lower in the diabetic subjects (p < 0.02), indicating that impaired dilation to increased flow was out of proportion to the impairment of the glyceryltrinitrate response in these subjects (15.6 +/- 5.6% vs. 19.7 +/- 6.6% in control subjects, p < 0.001). On multivariate analysis, flow-mediated dilation was inversely related to both duration of diabetes (r = -0.26, p < 0.05) and low density lipoprotein (LDL) cholesterol levels (r = -0.38, p < 0.005). CONCLUSIONS: Vascular reactivity is impaired in the systemic arteries of asymptomatic young adults with insulin-dependent diabetes and may represent early large-vessel disease. The degree of impairment is related to the duration of diabetes, and these patients appear particularly vulnerable to damage from LDL cholesterol, even at levels considered acceptable in nondiabetic subjects. |
| Impairment of endothelium-dependent relaxation in aorta from rats with arteriosclerosis induced by excess vitamin D and a high-cholesterol diet Kitagawa, S., Y. Yamaguchi, et al. (1992), Jpn J Pharmacol 59(3): 339-47. Abstract: The present investigation was undertaken to characterize the relaxing responsiveness in aortic strips from rats with arteriosclerosis, which was produced by excess vitamin D2 (VD) administration followed by treatment with or without a high-cholesterol diet for 6 weeks (VD + CHOL and VD group, respectively). This arteriosclerotic aorta was characterized by medial calcification and intimal cell proliferation. Helical strips of thoracic aorta were suspended in oxygenated Krebs-Henseleit solution. Under precontraction with noradrenaline, endothelium-dependent relaxations to acetylcholine were significantly attenuated in the VD and VD + CHOL as compared with the control. Relaxation to calcium ionophore A23187 was also significantly attenuated in the VD + CHOL. However, the relaxing responses to acetylcholine and A23187 in aortas from rats fed a high-cholesterol diet alone remained unaffected. Nitroglycerin caused an equal degree of relaxation in aortas from control and arteriosclerotic rats. There was a significant negative correlation between the relaxing response to acetylcholine and the calcium content in the aorta. These results indicate that in arteriosclerotic rat aortas, the endothelium-dependent relaxation to acetylcholine is impaired in proportion to the degree of calcification, and such impairment is facilitated by cholesterol feeding but can not be attributed to hypercholesterolemia or vascular cholesterol deposition. |
| Impairment of vascular function following BCG immunisation is associated with immune responses to HSP-60 in the cholesterol-fed rabbit Lamb, D. J., M. L. Tickner, et al. (2004), Atherosclerosis 172(1): 13-20. Abstract: An immune response to heat shock protein (HSP)-60/65 has recently been implicated in atherogenesis. The aim of this study was to determine whether this effect may be mediated by impairment of endothelial function. Rabbits were injected with bacillus Calmette-Guerin (BCG) vaccine (n=12) or saline (n=12). A further injection of BCG or saline was administered after 2 weeks. After a further 2 weeks, animals were fed either a 0.25-1% cholesterol diet or a chow diet for 16 weeks. Blood cholesterol levels were maintained at 10-12mmol/l by altering the dietary cholesterol content. Plasma levels of anti-mycobacterial antibodies rose following BCG immunisation, but anti-HSP antibodies developed only in the BCG-immunised, cholesterol-fed rabbits. Aortic endothelium from cholesterol-fed, but not chow-fed, rabbits stained positively for HSP-60, independently of the immunisation protocol. Endothelial function was impaired in the BCG immunised, cholesterol-fed rabbits as measured by acetylcholine-mediated relaxation of isolated non-atherosclerotic carotid artery rings (P<0.05). This impairment was positively associated with the level of plasma anti-HSP-60 antibodies (P<0.01). These results suggest that BCG immunisation impairs endothelial responses, at least in part, by immune responses against mycobacterial and vascular HSP. |
| Implication of cholesterol in cyclosporine pharmacodynamics in minimal change nephrotic syndrome Hirano, T., T. Kawamura, et al. (2003), Clin Pharmacol Ther 74(6): 581-90. Abstract: BACKGROUND: High blood cholesterol concentrations in patients with minimal change nephrotic syndrome may affect cyclosporine (INN, ciclosporin) pharmacodynamics and its clinical efficacy, but few attempts have been carried out to disclose this problem. METHODS: We evaluated the cellular pharmacodynamics of cyclosporine in 24 patients with minimal change nephrotic syndrome. In vitro cyclosporine concentrations yielding 50% inhibition (IC(50)) of blastogenesis of peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A were calculated. The relationships between the IC(50) values and laboratory data including serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations were examined. Clinical cyclosporine efficacy was assessed by a decreasing rate (percentage) of urinary protein 1 week after cyclosporine therapy. Percentages of LDL receptor-positive or CD3-positive PBMCs were evaluated with flow cytometry in 7 patients and 15 healthy subjects. RESULTS: The cyclosporine IC(50) values negatively correlated with the clinical cyclosporine efficacy assessed by a decreasing rate of urinary protein (r = -0.708, P =.0006). Cyclosporine IC(50) values significantly correlated with either serum total cholesterol (r = 0.681, P =.0003) or LDL cholesterol (r = 0.751, P =.0034) concentrations. Furthermore, serum total or LDL cholesterol levels significantly correlated negatively with clinical cyclosporine efficacy (r = -0.613, P =.0057, and r = -0.773, P =.0399, respectively). In 7 patients, serum total and LDL cholesterol concentrations were significantly higher than those of 15 healthy subjects (P <.005), whereas the percentages of LDL receptor-expressing cells in CD3-enriched PBMCs were not significantly different between these patients and healthy subjects. In addition, the cyclosporine IC(50) values and the percentages of LDL receptor-expressing PBMCs did not negatively correlate in either the patients or the healthy subjects. CONCLUSIONS: The data raised the possibility that hypercholesterolemia in patients with minimal change nephrotic syndrome attenuates cellular and clinical cyclosporine pharmacodynamics. Down-regulation of LDL receptor in T cells was not observed in these patients, and individual deviation of PBMC response to cyclosporine does not appear to be related to the difference of LDL receptor-positive cell numbers. |
| Implications of 2001 cholesterol treatment guidelines based on a retrospective analysis of a high-risk patient cohort Frolkis, J. P., G. L. Pearce, et al. (2002), Am J Cardiol 89(6): 765-6. |
| Implications of applying widely accepted cholesterol screening and management guidelines to a British adult population: cross sectional study of cardiovascular disease and risk factors Unwin, N., R. Thomson, et al. (1998), Bmj 317(7166): 1125-30. Abstract: OBJECTIVE: To compare the implications of four widely used cholesterol screening and treatment guidelines by applying them to a population in the United Kingdom. DESIGN: Guidelines were applied to population based data from a cross sectional study of cardiovascular disease and risk factors. SETTING: Newcastle upon Tyne, United Kingdom. SUBJECTS: General population sample (predominantly of European origin) of 322 men and 319 women aged 25-64 years. MAIN OUTCOME MEASURES: Proportions recommended for screening and treatment. METHODS: Criteria from the British Hyperlipidaemia Association, the British Drugs and Therapeutics Bulletin (which used the Sheffield table), the European Atherosclerosis Society, and the American national cholesterol education programme were applied to the population. RESULTS: Proportions recommended for treatment varied appreciably. Based on the British Drugs and Therapeutics Bulletin guidelines, treatment was recommended for 5.3% (95% confidence interval 2.9% to 7.7%) of men and 3.3% (1.5% to 5.3%) of women, while equivalent respective values were 4.6 (2.3 to 6.9) and 2.8 (1.0 to 4.6) for the British Hyperlipidaemia Association, 23% (18.4% to 27.6%) and 10.6% (7.3% to 14.0%) for the European Atherosclerosis Society, and 37.2% (31.9% to 42.5%) and 22.2% (17.6% to 26.8%) for the national cholesterol education programme. Only the British Hyperlipidaemia Association and Drugs and Therapeutics Bulletin guidelines recommend selective screening. Applying British Hyperlipidaemia Association guidelines, from 7.1% (4.3% to 9.9%) of men in level one to 56.7% (51.3% to 62.1%) of men in level three, and from 4.4% (2.1% to 6.7%) of women in level one to 54.4% (48.9% to 59.9%) of women in level three would have been recommended for cholesterol screening. Had the Drugs and Therapeutics Bulletin guidelines been applied, 22.2% (16.5% to 27.9%) of men and 12.2% (8. 6% to 15.8%) of women would have been screened. CONCLUSIONS: Without evidence based guidelines, there are problems of variation. A consistent approach needs to be developed and agreed across the United Kingdom. |
| Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Grundy, S. M., J. I. Cleeman, et al. (2004), J Am Coll Cardiol 44(3): 720-32. Abstract: The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C < 100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy. |
| Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro Bjorkhem, I., D. Lutjohann, et al. (1997), J Biol Chem 272(48): 30178-84. Abstract: The brain is the most cholesterol-rich organ in the body. Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. Very recently we showed that there is a continuous age-dependent flux of 24(S)-hydroxycholesterol from the human brain into the circulation (Lutjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Siden, A., Diczfalusy, U., and Bjorkhem, I. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9799-9804). Here we measured the rate of synthesis of cholesterol as well as the conversion of cholesterol into 24(S)-hydroxycholesterol in rat brain in vivo with use of an 18O2 inhalation technique and mass isotopomer distribution analysis. Cholesterol synthesis was found to correspond to 0.03 +/- 0.01% of the pool per h. Conversion of cholesterol into 24(S)-hydroxycholesterol was of a similar magnitude, about 0.02% of the pool per h. Brain microsomes converted endogenous cholesterol into 24(S)-hydroxycholesterol at a similar rate when incubated in the presence of NADPH. When incubated with whole homogenate and subcellular fractions of rat brain, there was no significant conversion of tritium-labeled 24-hydroxycholesterol into more polar products. Plasma from 18O2-exposed rats contained 24(S)-hydroxycholesterol with an enrichment of 18O similar to that in 24(S)-hydroxycholesterol in the brain. The results suggest that the present 24(S)-hydroxylase mediated mechanism is most important for elimination of cholesterol from the brain of rats. There is a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol with a rapid turnover of the small pool of the latter oxysterol due to leakage to the circulation (half-life of brain 24(S)-hydroxycholesterol is about 0.5 days as compared with 2-4 months for brain cholesterol). It is evident that the 24(S)-hydroxylation greatly facilitates transfer of cholesterol over the blood-brain barrier and that this hydroxylation may be critical for cholesterol homeostasis in the brain. |
| Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans Lund, E., O. Andersson, et al. (1996), Arterioscler Thromb Vasc Biol 16(2): 208-12. Abstract: We have recently demonstrated that cultured human alveolar macrophages efficiently convert cholesterol into excretable 27-oxygenated products. We show here that increasing the intracellular concentration of cholesterol by a factor of 10 leads to about a twofold increase in the excretion of 27-oxygenated products from cultured macrophages. Inhibition of the sterol 27-hydroxylase caused a significant intracellular accumulation of cholesterol. A direct comparison was made between flux of cholesterol and 27-oxygenated products from macrophages preloaded with 4-14Ccholesterol. Under the specific conditions employed with fetal calf serum in the culture medium, the flux of 27-oxygenated products was about 10% of that of cholesterol. Since the sterol 27-hydroxylase, which converts cholesterol to 27-oxygenated products, is present in many cell types, we suggest that 27-oxygenation is a general mechanism for removal of intracellular cholesterol. To evaluate this hypothesis, we measured the net uptake by the human liver of circulating 27-oxygenated products, which was found to be about 20 mg/24 h. This uptake corresponds to approximately 4% of the bile acid production, assuming quantitative conversion into bile acids. It is concluded that the 27-hydroxylase pathway is of significance for elimination of extrahepatic cholesterol. |
| Importance of age upon the increase in HDL2-cholesterol in the alcoholic Zentella de Pina, M., A. Diaz Belmont, et al. (1991), Arch Invest Med (Mex) 22(3-4): 323-7. Abstract: An inverse relationship has been found between high density lipoprotein cholesterol (HDL-C) and the incidence of coronary disease. A controversy exists in the international literature as to which sub-fraction, HDL2-C or DHL-C, rises after ethanol ingestion. This paper studies a comparison of the levels of circulating cholesterol, HDL-C, HDL2-C and HDL3-C in two groups: a control group of 44 healthy subjects who had no ethanol in over a year, and a second one made up off 40 chronic alcoholics, who consumed between 80 and 160 gr. of ethanol per day. The alcoholic population showed lower levels of cholesterol and higher levels of HDL-C, HDL2-C and HDL3-C. When compared with the control group, the increase was in alcoholics 58% for HDL2-C and 29% for HDL3-C. An analysis of the different age groups shows an increase of 110% in HDL2-C, in alcoholics between ages 31 and 40, as compared with their control group. An increase of 81% occurred between ages 51 and 60, but rarely rose 20% between ages 21 and 30, as well as between 51 and 60. The maximum rise of HDL3-C in drinkers, related to their control group, was 38% during the fourth decade of life. The conclusion is that the HDL2-C subfraction rises in chronic alcoholics, and the changes in other HDL-C subfractions are more useful when they are placed at the different individual's decades of age, than when taken from complete population samples. |
| Importance of dietary cholesterol for the maturation of mouse brain myelin Haque, Z. U. and Z. Mozaffar (1992), Biosci Biotechnol Biochem 56(8): 1351-4. Abstract: The effect of nil (control), 1% (CH-1) and 5% (CH-5) dietary cholesterol on the myelination of mouse brain, and its deposition in the heart and liver were investigated during infancy. Swiss Webstar female mice were given formulated diets from early gestation, and their pups were weaned on the same diet as that of the individual mothers up to 60 days after birth. The test diets increased the liver weight and cholesterol content compared to the control even in suckling pups (20 days), but did not significantly influence the heart weight until 60 days. The cholesterol content of the heart was not increased by the CH-1 diet throughout the feeding period, but it did increase the mole ratio of major myelin lipids and hastened its maturation. Myelin cholesterol was 10% higher in 20-day-old suckling pups in the CH-5 group compared to the control. Data indicate that dietary cholesterol altered the brain myelination rate of weaning mice, and that the mother's dietary cholesterol influenced myelination of the suckling pups. |