| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1 Accad, M., S. J. Smith, et al. (2000), J Clin Invest 105(6): 711-9. Abstract: Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences. |
| Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice Ishibashi, S., J. L. Goldstein, et al. (1994), J Clin Invest 93(5): 1885-93. Abstract: Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR-/- mice) were fed a diet that contained 1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with a marked increase in VLDL, intermediate density lipoproteins (IDL), and LDL cholesterol, and a decrease in HDL cholesterol. In wild type littermates fed the same diet, the total plasma cholesterol remained < 160 mg/dl. After 7 mo, the LDLR-/- mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. No such changes were seen in the LDLR-/- mice on a normal chow diet, nor in wild type mice that were fed either a chow diet or the high-fat diet. We conclude that LDL receptors are largely responsible for the resistance of wild type mice to atherosclerosis. The cholesterol-fed LDLR-/- mice offer a new model for the study of environmental and genetic factors that modify the processes of atherosclerosis and xanthomatosis. |
| Mast cell chymase degrades apoE and apoA-II in apoA-I-knockout mouse plasma and reduces its ability to promote cellular cholesterol efflux Lee, M., L. Calabresi, et al. (2002), Arterioscler Thromb Vasc Biol 22(9): 1475-81. Abstract: OBJECTIVE: Mast cell chymase is a chymotryptic heparin proteoglycan-bound neutral protease that exerts its activity in extracellular fluids. We studied the effect of chymase on the apolipoprotein compositions and the abilities of plasmas from apolipoprotein (apo)A-I-knockout (A-I-KO) and wild-type (C57BL/6J) mice to stimulate efflux of cellular cholesterol from mouse macrophage foam cells. METHODS AND RESULTS: The A-I-KO apolipoproteins compared with the wild-type (apoA-I, apoA-II, apoA-IV, and apoE) showed total lack of apoA-I, unaltered apoA-II, an absence of apoA-IV, and an increase of apoE. Despite these major differences, the 2 plasmas induced similar high-affinity efflux of cholesterol from the foam cells. Quantitative analysis of chymase-treated plasmas revealed (1) in A-I-KO plasma, complete loss of apoE and apoA-II, and (2) in wild-type plasma, slight reduction of apoA-I associated with complete depletion of the minor pre-beta-high density lipoprotein fraction, strong reduction of apoA-II, and complete depletion of apoA-IV and apoE. Both proteolyzed plasmas had lost the ability to induce cellular cholesterol efflux with high affinity. Addition of discoidal pre-beta-migrating reconstituted high density lipoprotein particles containing human apoA-I or apoA-II to the chymase-treated A-I-KO plasma fully restored its cholesterol efflux-inducing ability, indicating functional replacement of the proteolyzed apoE and apoA-II. Thus, chymase degraded all the nondeleted apolipoproteins of the A-I-KO plasma involved in the high-affinity efflux of cellular cholesterol. CONCLUSIONS: This is the first indication that genetically engineered mice could be used as models for examining the hypothesis that extracellular proteases are involved in the development of atherosclerosis by inhibiting the apolipoprotein-mediated removal of macrophage cholesterol. |
| Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol Lee, M., C. P. Sommerhoff, et al. (2002), Arterioscler Thromb Vasc Biol 22(12): 2086-91. Abstract: OBJECTIVE: In human atherosclerotic lesions, degranulated mast cells are found in the vicinity of macrophage foam cells. Mast cell granules contain tryptase, a tetrameric serine protease requiring glycosaminoglycans for stabilization. No endogenous inhibitors have been described for tryptase, and the physiological functions of the enzyme are poorly understood. Here, we investigated the effects of human tryptase on the integrity of high density lipoprotein (HDL)3 and on its ability to release cholesterol from cultured mouse macrophage foam cells. METHODS AND RESULTS: Incubation of HDL3 with tryptase led to degradation of its apolipoproteins. Tryptase predominantly degraded a quantitatively minor subfraction of HDL3 that is lipid poor, exhibits electrophoretic pre-beta mobility, and contains either apolipoprotein A-I or apolipoprotein A-IV as its sole apolipoprotein. Moreover, tryptase caused functional changes in HDL3 by destroying its ability to promote high-affinity efflux of cholesterol from macrophage foam cells, ie, the pre-beta-HDL-dependent component of the process. Human aortic proteoglycans increased the ability of tryptase to proteolyze HDL3, suggesting that the proteoglycan-rich extracellular matrix of the arterial intima provides an appropriate environment for the extracellular actions of tryptase. CONCLUSIONS: By depleting pre-beta-HDL, mast cell tryptase may impair the initial step of reverse cholesterol transport and will then favor cellular accumulation of cholesterol during atherogenesis. |
| Mast cell-mediated inhibition of reverse cholesterol transport Lee, M., L. K. Lindstedt, et al. (1992), Arterioscler Thromb 12(11): 1329-35. Abstract: Net cholesterol efflux from cholesterol-loaded macrophages, i.e., foam cells, was induced by incubating the foam cells with high density lipoprotein3 (HDL3). However, when the incubation system included rat serosal mast cells stimulated to trigger exocytosis of their cytoplasmic secretory granules, the ability of HDL3 to induce cholesterol efflux was largely lost. This loss was found to be due to the proteolytic action of chymase, the neutral protease of the granules, which degraded the apolipoproteins of HDL3, so rendering them unable to mediate cholesterol efflux from the foam cells. The observation defines a novel cell-dependent mechanism that blocks the initial steps of reverse cholesterol transport and suggests a role for mast cell chymase in cellular accumulation of cholesterol, an early stage in atherogenesis. |
| Mastoid cholesterol granuloma with intracranial invasion Novo Ruiz, J. J., G. Videgain, et al. (2002), Acta Otorrinolaringol Esp 53(4): 285-8. Abstract: We report a case of antral-mastoid cholesterol granuloma, invading the middle cranial fossa, clinically showing a sudden onset of neurological symptoms. The histopathologic, diagnostic, and therapeutic aspects of this lesion are commented. |
| Maternal acceptability of a dietary intervention designed to lower children's intake of saturated fat and cholesterol: the Dietary Intervention Study in Children (DISC) Reimers, T. M., K. M. Brown, et al. (1998), J Am Diet Assoc 98(1): 31-4. Abstract: OBJECTIVE: This report examined the acceptability to mothers of a dietary educational and behavioral intervention for preadolescent children with elevated levels of serum low-density lipoprotein cholesterol (LDL-C) who were enrolled in the Dietary Intervention Study in Children (DISC). DESIGN: DISC is a randomized, controlled clinical trial. Subjects were randomly assigned to either an intervention or usual-care (control) group. SUBJECTS/SETTING: To be eligible for the study, participants were required to have the average of 2 fasting LDL-C values fall between the 80th and 98th sex-specific percentiles. Three hundred thirty-four 8-to 10-year-old children and their families were randomly assigned to an intervention group, and 329 were assigned to a usual-care (control) group. This study examined data from 232 subjects in the intervention group. Data were collected at 6 intervention sites around the United States. INTERVENTION: Those assigned to the intervention group participated in a multidisciplinary dietary intervention that included a series of group and individual sessions over a 3-year period. Children and their caretakers were taught to follow a nutritionally adequate diet that was low in total fat, saturated fat, and cholesterol and high in polyunsaturated fat. MAIN OUTCOME MEASURES: Three nonconsecutive 24-hour diet recalls were collected at baseline and at 1 year by trained and certified dietitians. A questionnaire designed to assess diet acceptability was administered at months 4, 8, 11, and 15. Demographic measures were collected at the onset of the study. STATISTICAL ANALYSIS PERFORMED: Statistical procedures included factor analysis and regression analysis. RESULTS: Regression analysis suggested that perceived effectiveness of the dietary intervention and mothers' having few concerns about disadvantages of the diet were significantly related to higher overall fat intake in children in one-parent families. Maternal willingness to implement the diet was significantly related to lower saturated fat intake. APPLICATIONS/CONCLUSIONS: In attempts to change eating behavior of children, interest and cooperation of the parents are essential to achieving successful results. These analyses further suggest that maternal acceptability translates into willingness to implement the diet and may facilitate changes that are associated with reduced saturated fat intake in children. |
| Matrix effects and the accuracy of cholesterol analysis Ross, J. W., G. L. Myers, et al. (1993), Arch Pathol Lab Med 117(4): 393-400. Abstract: We found evidence of bias due to matrix effect in 70% of 37 instrument/reagent-specific systems analyzing the total cholesterol content of a lyophilized proficiency testing material. We used a computational method to remove bias due to matrix effect from the proficiency testing database. After correction for matrix effect bias and when compared with the reference method, 92% to 93% of results for three lyophilized proficiency testing samples analyzed in 1989 and 1990 met the 1992 National Cholesterol Education Program total error goal of 8.9%, and 94% to 95% met the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) goal of 10%. However, compared with the definitive method for total cholesterol, the calibration bias of 41% of 37 peer groups exceeded the 1992 National Cholesterol Education Program goal for bias of 3%. Because the calibration bias of the method is incorporated into the peer group mean, use of peer group means as target values to assess result acceptability hinders advancement of the state of the art in interlaboratory comparability and the clinical effectiveness of laboratory testing. The prevalence of matrix effects has prevented successful application of accuracy-based evaluation of cholesterol test proficiency. The establishment of predictable recovery, preferably complete recovery, of cholesterol from reference materials is an important priority for cholesterol test methods. However, adjustment of proficiency testing results to remove the average bias due to matrix effects can help assess the actual state of the art in cholesterol test accuracy. |
| Matrix effects on proficiency testing materials. Impact on accuracy of cholesterol measurement in laboratories in the nation's largest hospital system Naito, H. K., Y. S. Kwak, et al. (1993), Arch Pathol Lab Med 117(4): 345-51. Abstract: The objective of this collaborative study with the Department of Veterans Affairs (VA), College of American Pathologists (CAP), and the Centers for Disease Control and Prevention (CDC) was to quantitate the matrix-induced biases of cholesterol measurements on the CAP Comprehensive Chemistry Surveys materials used in proficiency testing (PT). A total of 174 VA Medical Centers outpatient clinics and clinical laboratories participate in the VA-CDC National Cholesterol Standardization and Certification Program. This study was conducted in 112 VA laboratories that have been standardized for measuring cholesterol accurately (within +/- 3.0% of the CDC reference-method values) using fresh, unfrozen, unadulterated human serum samples. Fresh serum samples and 1990 CAP Surveys materials were sent by overnight mail, and the laboratories were asked to analyze them simultaneously in triplicate in a single analytic batch run. The results showed significant matrix-effect biases with the CAP Surveys materials with six of the eight major peer groups, despite the fact that accuracy of cholesterol measurements was maintained with fresh serum samples. The magnitude and direction (positive or negative) of the matrix-effect biases were instrument, reagent, and method specific using the following peer groups: du Pont Dimension (-8.9%); Beckman CX4, CX5, and CX7 (-5.5%); Kodak Ektachem 400, 500, and 700 (+4.4%); Instrumentation Laboratory Monarch (-3.1%); Baxter Paramax (-2.4%); Technicon SMAC and RA (+1.3%); Hitachi/BMD 704 through 747 (+0.4%); and Abbott Spectrum (-0.3%). The CAP PT materials used currently do not behave in a manner identical to fresh human serum when measuring cholesterol on many, but not all, analytic systems. The observed biases due to "matrix effects" with PT materials will cause incorrect conclusions about the accuracy of many laboratory procedures performed on fresh patient specimens. This matrix-effect phenomenon will severely hamper interlaboratory accuracy transfer, standardization efforts, and monitoring performance of a laboratory's testing accuracy with the use of the current survey materials used in PT programs. Collaborative efforts are needed to (1) improve PT fluids to analytically behave more like fresh, human serum; (2) improve instrument design and reagent formulation; and (3) select methods and methodologic parameters that are more "robust" and less sensitive to the exact character of processed calibrators, quality control, and PT materials. |
| Matrix metalloproteinases-3, -7, and -12, but not -9, reduce high density lipoprotein-induced cholesterol efflux from human macrophage foam cells by truncation of the carboxyl terminus of apolipoprotein A-I. Parallel losses of pre-beta particles and the high affinity component of efflux Lindstedt, L., J. Saarinen, et al. (1999), J Biol Chem 274(32): 22627-34. Abstract: Matrix metalloproteinases (MMPs) have been suggested to function in remodeling of the arterial wall, but no information is available on their possible role in early atherogenesis, when cholesterol accumulates in the cells of the arterial intima, forming foam cells. Here, we incubated the major component responsible for efflux of cholesterol from foam cells, high density lipoprotein 3 (HDL(3)), with MMP-1, -3, -7, -9, or -12 at 37 degrees C before adding it to cholesterol-loaded human monocyte-derived macrophages. After incubation with MMP-3, -7, or -12, the ability of HDL(3) to induce the high affinity component of cholesterol efflux from the macrophage foam cells was strongly reduced, whereas preincubation with MMP-1 reduced cholesterol efflux only slightly and preincubation with MMP-9 had no effect. These differential effects of the various MMPs were reflected in their differential abilities to degrade the small pre-beta migrating particles present in the HDL(3) fraction. NH(2)-terminal sequence and mass spectrometric analyses of the apolipoprotein (apo) A-I fragments generated by MMPs revealed that those MMPs that strongly reduced cholesterol efflux (MMPs-3, -7, and -12) cleaved the COOH-terminal region of apoA-I and produced a major fragment of about 22 kDa, whereas MMPs-1 and -9, which had little and no effect on cholesterol efflux, degraded apoA-I only slightly and not at all, respectively. These results show, for the first time, that some members of the MMP family can degrade the apoA-I of HDL(3), so blocking cholesterol efflux from macrophage foam cells. This expansion of the substrate repertoire of MMPs to include apoA suggests that these proteinases are directly involved in the accumulation of cholesterol in atherosclerotic lesions. |
| MaxEPA fish oil enhances cholesterol-induced intimal foam cell formation in rabbits Rogers, K. A. and R. Adelstein (1990), Am J Pathol 137(4): 945-51. Abstract: In this study, the cholesterol-fed rabbit model was used to test the hypothesis that fish oil supplementation can influence the initiation and development of atherosclerotic lesions. Rabbits were fed one of two diets for a period of 30 days: a nonatherogenic diet with corn oil as the sole fat source, or an atherogenic diet containing beef tallow and cholesterol. In addition, animals received a daily supplement of either MaxEPA fish oil or corn oil (0.5 ml/kg body weight). Terminal blood samples were drawn and the cholesterol and triglyceride levels determined for both plasma and very low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density (HDL) lipoproteins. Thiobarbituric acid-reacting substance (TBARS), an indicator of lipid peroxidation, was measured in the plasma samples. Besides these biochemical parameters of atherogenesis, the number of intimal foam cells in the descending thoracic aorta of each animal was determined by microscopic examination of the vessels en face. In rabbits fed the nonatherogenic diet, fish oil supplementation did not significantly affect any of the biochemical parameters that were measured. In contrast, fish oil supplementation of the atherogenic diet led to a significant increase in the LDL- and HDL-cholesterol as well as the HDL-triglyceride levels. Plasma TBARS also increased more than four times. Morphologic analysis of the vessels from rabbits fed the atherogenic diet indicated that fish oil supplementation led to a threefold increase in the number of intimal foam cells, a result that may be linked to increases in both LDL-cholesterol and plasma TBARS. The results of these experiments do not support the hypothesis that dietary fish oil will inhibit the initiation or progression of lesion formation in the cholesterol-fed rabbit. |
| Maximal response to a plasma cholesterol-lowering diet is achieved within two weeks Hodson, L., C. M. Skeaff, et al. (2002), Nutr Metab Cardiovasc Dis 12(5): 291-5. Abstract: BACKGROUND AND AIM: Replacing saturated fat with polyunsaturated fat reduces plasma cholesterol concentrations; however, it has not been well documented how rapidly the decline occurs nor how long is required to reach the maximum cholesterol-lowering effect. The aim of the present study was to determine the time course of change in plasma cholesterol concentrations when participants adopt a lipid-lowering diet. METHODS AND RESULTS: Participants (n = 19) were asked to follow for 19 days a diet high in saturated fat and then crossed over--without washout--for 19 days to a diet high in n-6 polyunsaturated fat. Participants were asked to maintain a total fat intake of 30-33% of total energy on both diets. Energy and nutrient intakes were assessed by self-reported food records covering 3 days. Plasma total cholesterol concentrations were measured on days 0, 1, 2, 5, 8, 12, and 19 of the n-6 polyunsaturated fat rich diet. Mean (95% CI) plasma total cholesterol concentration declined from 5.10 mmol/L (4.77, 5.46) at day 0 to 4.25 mmol/L (3.83, 4.67) on day 12 and remained unchanged at 4.23 mmol/L (3.85, 4.61) on day 19. A statistically significant decrease in plasma cholesterol concentration was achieved on day 2 of the intervention; by day 5, 59% (0.51 mmol/L) of the maximum reduction (0.87 mmol/L) had been reached. CONCLUSIONS: Adopting a lipid lowering diet initiates an immediate decline in plasma cholesterol concentration, the full effect of which is achieved within two weeks. |
| Maximizing recruitment efforts in a drug lipid-lowering trial with dietary intervention to lower LDL cholesterol Dolecek, T. A., K. H. Bradham, et al. (1996), Control Clin Trials 17(1): 33-45. Abstract: A select group of screened applicants initially disqualified from a four-center, primary prevention drug lipid-lowering trial because of borderline elevated serum low-density lipoprotein cholesterol (LDL-C) levels, as defined in National Cholesterol Education Program-Adult Treatment Panel I (NCEP-ATP I) guidelines, participated in a dietary intervention protocol that was incorporated into the screening phase of the trial. Seventy-seven screened applicants for the Asymptomatic Carotid Artery Progression Study entered the dietary program, which was overseen by an experienced registered dietitian at the central operations sites who collaborated with local staff at clinical sites during program implementation. NCEP-ATP I fat-modified step I diet specifications served as the basis for the intervention. The program, consisting of five sessions conducted over an 8-week period, primarily used written and audiovisual educational materials in combination with behavioral approaches. Of the original 77 participants, 36 responded to the intervention by achieving their LDL-C goal. Twenty-nine were nonresponders and 12 were dropouts. Responders achieved an average 11.7% drop in total cholesterol at the end of the 8-week program. Mean LDL-C decline paralleled total cholesterol change. High-density lipoprotein cholesterol also decreased significantly. These results were sustained for 24 of the responders attending the final screening visit approximately a month later, when another fasting blood lipid measurement was made. Participants who dropped out were more likely to be smokers. Pre- and postintervention nutrition data assessed by semiquantitative food frequency questionnaire for 20 screenees randomized into the study indicated significant reductions in total fat, saturated fat, polyunsaturated fat, and dietary cholesterol, all known to influence blood lipid levels. Similar programs may prove useful to other drug lipid-lowering trials to maximize recruitment efforts. |
| Maximum solubility of cholesterol in phosphatidylcholine and phosphatidylethanolamine bilayers Huang, J., J. T. Buboltz, et al. (1999), Biochim Biophys Acta 1417(1): 89-100. Abstract: In any lipid bilayer membrane, there is an upper limit on the cholesterol concentration that can be accommodated within the bilayer structure; excess cholesterol will precipitate as crystals of pure cholesterol monohydrate. This cholesterol solubility limit is a well-defined quantity. It is a first-order phase boundary in the phospholipid/cholesterol phase diagram. There are many different solubility limits in the literature, but no clear picture has emerged that can unify the disparate results. We have studied the effects that different sample preparation methods can have on the apparent experimental solubility limit. We find that artifactual demixing of cholesterol can occur during conventional sample preparation and that this demixed cholesterol may produce artifactual cholesterol crystals. Therefore, phospholipid/cholesterol suspensions which are prepared by conventional methods may manifest variable, falsely low cholesterol solubility limits. We have developed two novel preparative methods which are specifically designed to prevent demixing during sample preparation. For detection of the cholesterol crystals, X-ray diffraction has proven to be quantitative and highly sensitive. Experiments based on these methods yield reproducible and precise cholesterol solubility limits: 66 mol% for phosphatidylcholine (PC) bilayers and 51 mol% for phosphatidylethanolamine (PE) bilayers. We present evidence that these are true, equilibrium values. In contrast to the dramatic headgroup effect (PC vs. PE), acyl chain variations had no effect on the cholesterol solubility limit in four different PC/cholesterol mixtures. |
| May plasma cholesterol level be considered a neoplastic marker in liver disease from cirrhosis to hepatocellular carcinoma? Venturini, I., R. Amedei, et al. (1999), Ital J Gastroenterol Hepatol 31(1): 61-5. Abstract: BACKGROUND: Although the role of cholesterol in tumourigenesis is unclear, it is used by the tumoural cells for biosynthetic processes and for steroid synthesis. AIM: To accertain whether plasma cholesterol levels might be a reliable neoplastic marker of a developing hepatocellular carcinoma in patients with liver cirrhosis. PATIENTS: Plasma cholesterol has been studied in 287 liver cirrhosis patients without hepatocellular carcinoma and in 132 patients with hepatocellular carcinoma. RESULTS: Cholesterol (mean +/- SEM) was higher in hepatocellular carcinoma patients when compared with age-, sex- and Child-Pugh class matched cirrhotic controls. In Child-Pugh class A, B and C with uncomplicated liver cirrhosis these values were, respectively, 142.0 +/- 2.5, 117.3 +/- 2.5, 97.4 +/- 2.9 vs 172.5 +/- 4.7, 163.8 +/- 7.9, 153.5 +/- 8.0 +/- mg/dl in patients with hepatocellular carcinoma (p < 0.001). A significant increase of cholesterol (p < 0.001) has been reported in the patients with liver cirrhosis when complicated by hepatocellular carcinoma and it was not related to cholestasis. CONCLUSIONS: This observation seems to suggest that the enhanced cholesterol biosynthesis by tumoural cells leads to a rise in plasma cholesterol of patients with cancer, and, moreover, that, this increase may be used as a neoplastic marker indicating the development of a tumour in patients with liver cirrhosis. |
| MDR1, cholesterol certification and cell growth: a comparative study in normal and multidrug-resistant KB cell lines Pani, A., B. Batetta, et al. (2000), Cell Mol Life Sci 57(7): 1094-102. |
| MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis Rosmorduc, O., B. Hermelin, et al. (2001), Gastroenterology 120(6): 1459-67. Abstract: BACKGROUND & AIMS: Many studies indicate that gallstone susceptibility has genetic components. MDR3 is the phosphatidylcholine translocator across the hepatocyte canalicular membrane. Because phospholipids are a carrier and a solvent of cholesterol in hepatic bile, we hypothesized that a defect in the MDR3 gene could be the genetic basis for peculiar forms of cholesterol gallstone disease, in particular those associated with symptoms and cholestasis without evident common bile duct stone. METHODS: We studied 6 adult patients with a peculiar form of cholelithiasis. MDR3 gene sequence was determined by reverse-transcription polymerase chain reaction amplification of mononuclear cell RNAs followed by direct sequencing. Hepatic bile was analyzed in 2 patients. RESULTS: All patients shared the following features: at least 1 episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of chronic cholestasis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by ursodeoxycholic acid therapy. Hepatic bile composition showed a high cholesterol/phospholipid ratio and cholesterol crystals. In all patients, we found MDR3 gene mutations involving a conserved amino acid region. CONCLUSIONS: These preliminary observations suggest that MDR3 gene mutations represent a genetic factor involved in this peculiar form of cholesterol gallstone disease in adults. They require further studies to assess the prevalence of MDR3 gene defects in symptomatic and silent cholesterol gallstone disease. |
| Meal-frequency effects on plasma hormone concentrations and cholesterol synthesis in humans Jones, P. J., C. A. Leitch, et al. (1993), Am J Clin Nutr 57(6): 868-74. Abstract: To examine meal-frequency effects on circulating hormone concentrations and cholesterol synthesis, male subjects consumed liquid diets given as either six evenly spaced (ES) or three diurnal (DI) meals over 3 d. Deuterium oxide was given on day 2 and blood sampled every 4 h over days 2 and 3 to measure plasma cholesterol, glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) concentrations and cholesterol synthesis. Cholesterol synthesis was determined from deuterium incorporation into plasma free cholesterol by using constrained and unconstrained curve-fit models. Plasma total cholesterol concentrations decreased in both ES and DI groups (P < 0.05). The ES group had lower insulin (P < 0.05) and GIP (P < 0.001) concentrations compared with the DI group. Cholesterol synthesis was reduced (P < 0.01) in the ES vs the DI group when determined by using constrained (0.050 +/- 0.002 vs 0.075 +/- 0.005 pools/d, respectively) and unconstrained (0.072 +/- 0.005 vs 0.119 +/- 0.011 pools/d, respectively) models. These data suggest meal frequency-dependent control of cholesterogenesis via hormonally mediated mechanisms. |
| Measurement of apolipoprotein A1 in cholesterol gallstones and gallbladder bile of patients with gallstones Hasegawa, T. and I. Makino (1995), J Gastroenterol 30(1): 96-102. Abstract: Biliary apolipoprotein A1 in bile inhibits the nucleation of cholesterol crystals from bile super-saturated with cholesterol. In the present study, using an enzyme-linked immunosorbent assay of apolipoprotein A1, we determined the content of apolipoprotein A1 in cholesterol gallstones and samples of gallbladder bile collected simultaneously from 23 patients during cholecystectomy. Protein content in cholesterol gallstones ranged from 50 to 5700 micrograms/g, with median, quartile, and three quartile values being 250, 111, and 740; apolipoprotein A1 content ranged from 9 to 9000 ng/g (200, 41, 647). The gallbladder bile samples contained protein at concentrations of 0.4-9.0 mg/ml (2.0, 1.1, 3.2), while apolipoprotein A1 was present at concentrations of 2.0-136.0 micrograms/ml (30.0, 10.0, 90.0). A notable finding was that the A1/total protein (TP) values for gallbladder bile, which ranged from 0.13% to 6.80% (1.62, 0.89, 3.34), were several times higher than those determined for gallstone samples, which ranged from 0.01% to 1.2%, 2% (0.06, 0.02, 0.25). The results of sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed that the protein profile in cholesterol gallstones was similar to that in gallbladder bile. It was concluded that: (1) the protein contained in gallstones may originate from bile, (2) the content of apolipoprotein A1 in cholesterol gallstones is only a trace amount, compared with that in gallbladder bile, and (3) biliary apolipoprotein A1 may be retained in a soluble phase in gallbladder bile, with minimal precipitation onto the surfaces of gallstones. |
| Measurement of apolipoprotein B as a screening test for identifying children with elevated levels of low-density lipoprotein cholesterol Dennison, B. A., D. A. Kikuchi, et al. (1990), J Pediatr 117(3): 358-63. Abstract: We compared the efficacy of two screening tests, measurement of apolipoprotein B (apo B) levels and measurement of serum total cholesterol levels, in detecting elevated low-density lipoprotein cholesterol (LDL-C) values in children. We studied 2850 children, aged 5 to 17 years, who had fasting lipid, lipoprotein, and apolipoprotein levels measured as part of the Bogalusa Heart Study. The test characteristics of apo B were superior to those of serum total cholesterol in screening children to detect elevated levels of LDL-C (greater than or equal to 95th percentile) and moderately elevated LDL-C levels (greater than or equal to 80th percentile). Unusually high or low values of high-density lipoprotein cholesterol are responsible for most of the misclassification that occurs when measurement of total cholesterol is used as a screening test for identifying children with elevated levels of LDL-C. This confounding effect of high-density lipoprotein cholesterol was eliminated when measurement of apo B levels was used as a screening test. Because the apo B test is more specific at a given sensitivity than the total cholesterol test, the apo B test can cost more and still be less expensive as a screening strategy. As the methods for determining apolipoprotein levels become standardized and readily available, the measurement of apolipoproteins could be developed into superior screening tests for the identification of patients with dyslipidemias. |