| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Distribution of lipoprotein phenotypes, cholesterol, and lipids in inner-city blacks Foster, P. and M. Jackson (1993), J Natl Med Assoc 85(3): 211-5. Abstract: Lipoprotein phenotypes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride levels were obtained from blood samples of 189 patients attending the Drew Hamilton Clinic in Central Harlem, New York, between 1987 and 1988. The study population ranged in age from 7 to 88 years; 135 of the patients were females and 54 were males. A difference in distribution of lipoprotein phenotypes was observed compared with the general population of the United States. Sixty-seven percent of blacks in this study were Type IIA compared with an estimated 10% of the general US population. Differences also were observed for blacks versus the general US population for Type IV (24% versus 45%), Type IIB (9% versus 40%), and Type V (0% versus 5%). Types I and III were rare in both groups (0% versus < 1%). The increased frequency of Type IIA among this predominantly black inner-city population may have implications for treatment strategies and prognostic value for predicting the risk of coronary heart disease. |
| Distribution of mixtures of bile salt taurine conjugates between lecithin-cholesterol vesicles and aqueous media: an empirical model Heuman, D. M. (1997), J Lipid Res 38(6): 1217-28. Abstract: Bile salts are surfactants that partition into phospholipid bilayers. When liposomes or membranes are exposed to mixed solutions of bile salts, the more hydrophobic bile salt species associate preferentially with the lipid bilayer. As a consequence, in the aqueous phase, the free monomeric concentration of bile salt declines and the more hydrophilic species become relatively enriched. Above a critical saturating concentration of lecithin-associated bile salt, a phase transition occurs with loss of membrane integrity and formation of mixed micelles. In this paper we present a quantitative model which, for mixed solutions of bile salt taurine conjugates, predicts the distribution of bile salt monomers between large unilamellar vesicles composed of lecithin and cholesterol and the aqueous phase. The model is based on association isotherms for individual bile salts, determined by an ultrafiltration method with empirical curve fitting, and is critically dependent upon the observation that association coefficients of each bile salt are a function of the total bound bile salt/lecithin mole ratio. Given the concentrations of individual bile salts, lecithin and cholesterol, the model permits calculation of the membrane-bound bile salt/lecithin ratio and the concentration of each bile salt remaining free as soluble monomer in the aqueous phase, as well as the overall hydrophilic-hydrophobic balance (hydrophobicity index) of the bile salts remaining free in aqueous solution. Distribution data determined empirically for a variety of mixtures of bile salt taurine conjugates and large unilamellar vesicles of varying cholesterol:lecithin ratio agree closely with predictions. This model may be of value in predicting the physical, biological and toxic properties of mixed bile salt solutions. |
| Distribution of phosphatidylcholine molecular species between mixed micelles and phospholipid-cholesterol vesicles in human gallbladder bile: dependence on acyl chain length and unsaturation Booker, M. L., W. W. LaMorte, et al. (1992), J Lipid Res 33(10): 1485-92. Abstract: The partitioning of phosphatidylcholine (PC) molecular species between mixed micelles and vesicles was studied in each of seven human gallbladder biles. Biles were fractionated by Sephacryl S-300 SF gel filtration chromatography, and PC species in the micellar and vesicular fractions were quantitated by high performance liquid chromatography. Micelles were enriched in species containing unsaturated acyl groups (e.g., 16:1-18:2, 18:1-18:2, and 18:1-18:3); vesicles were enriched in more highly saturated species (e.g., 16:0-16:1, 16:0-18:1, and 18:0-18:1). Separate multivariate analyses for each bile demonstrated that the distribution of PC species between vesicles and micelles was related to the degree of sn-1 and sn-2 unsaturation, and sn-1, but not sn-2, chain length. In addition, the tendency to partition into the micellar phase was particularly marked when unsaturation was present at both the sn-1 and sn-2 positions. When this interaction was included in the multivariate analyses, the regression models accounted for virtually all of the variation in PC partitioning (for each of the seven patients r2 = 0.92-0.98, P less than 0.03). These results suggest that the partitioning of PC species between micelles and vesicles is strictly determined by sn-1 chain length and the degree of unsaturation at both the sn-1 and sn-2 positions. In light of recent reports that fatty acyl composition influences the cholesterol content of vesicles and micelles in model biles, these results raise the possibility that diet-induced alterations in the phospholipid species and the relative proportions of biliary lipid particles may influence the cholesterol-carrying capacity of bile. |
| Distribution of serum total cholesterol in a population with varying risks of cardiovascular disease Anderson, P., A. Voss, et al. (1990), Ugeskr Laeger 152(8): 523-6. Abstract: By means of search in the literature and subsequent meta-analysis, the authors have described the serum total cholesterol values in three different risk groups for cardiovascular disease. High total serum cholesterol levels were associated with increased risk for cardiovascular disease. In addition, it was found that serum total cholesterol increases with age in all groups. A distinct sex difference was observed in the majority of investigations: in the age groups under 25 years and over 50 years, women have higher serum total cholesterol values than men while, in the age group 25-50 years, men have higher values than women. In addition, administration of hormones produces higher serum total cholesterol levels in young women but lower serum total levels among older women. In Danish investigations of serum total cholesterol, the level of serum total cholesterol corresponds to the serum total cholesterol levels in high and middle risk groups for cardiovascular disease. |
| Distribution of unesterified cholesterol-containing particles in human atherosclerotic lesions Sarig, S., W. H. Utian, et al. (1995), Am J Pathol 146(1): 139-47. Abstract: The objective of the study was to characterize unesterified cholesterol particles in human aorta and to correlate the findings with the severity of aortic atherosclerosis. Human tissues were processed under conditions that preserve deposits of unesterified cholesterol agglomerates. Filipinfluorescence was determined by using a novel triple band pass filter. The pattern of unesterified cholesterol deposits was age related and correlated with the severity of atherosclerosis. We found three types of deposits: 1), small spherulites (3 to 5 mu), which were depicted in both the media and intima in individuals as early as age 16, and which, in more advanced ages, showed an increase in density and a tendency to aggregate extracellularly throughout the intima in clusters; 2), elongated structures (10 to 30 mu in the middle zone of the intima), the density of which was directly related to the severity of atherosclerosis; and 3), large (100 mu), irregular deposits found mainly in the core of atherosclerotic plaques. The medium size deposits, compared with those found in the core of atherosclerotic plaques, retain their overall size (10 to 30 mu), uniformity (oval elongated), and localization (middle zone of the intima). On the basis of these observations we hypothesize cholesterol deposition in two stages of aggregation: 1), early degradation of infiltrating low density lipoprotein particles forming unesterified cholesterol-rich vesicles in the vessel wall, followed by aggregation to spherulites in the lower part of the intima; and 2), more massive agglomeration of particles containing unesterified cholesterol and calcium phosphate in the midzone of the intima. Because in the second stage of aggregation the transition of cholesterol to the solid state has already occurred, it is irreversible. |
| Distribution of waist-to-hip ratio, other indices of body fat distribution and obesity and associations with HDL cholesterol in children and young adults aged 4-19 years: The Third National Health and Nutrition Examination Survey Gillum, R. F. (1999), Int J Obes Relat Metab Disord 23(6): 556-63. Abstract: BACKGROUND: Little data has been published on the association of indices of body fat distribution and HDL cholesterol (HDL), a risk factor for cardiovascular morbidity, in representative samples of total populations of children and adolescents including blacks and Hispanics. OBJECTIVE: To describe the distribution of waist-to-hip ratio (WHR) in US children and adolescents and to assess the association with HDL. DESIGN: Cross-sectional survey of a large national sample, the Third National Health and Nutrition Examination Survey. PARTICIPANTS: People aged 4-19 y. MEASUREMENTS: Body circumferences, skinfold thickness, body mass index (BMI), and serum total and HDL cholesterol concentrations. RESULTS: Mean WHR varied consistently with age, gender, and ethnic group. Levels were highest in Mexican Americans. WHR showed significant negative associations with HDL cholesterol concentration and positive associations with the ratio of total serum cholesterol to HDL in pre- and postpubertal girls independent of age and BMI. However, associations were often not as strong as those with BMI. Other indices of body fat distribution were not superior to WHR. CONCLUSION: Further research is needed on the association of WHR, other indices of body fat distribution and HDL measured in childhood with subsequent risk of atherosclerosis. |
| Disturbances in cholesterol metabolism Marschall, H. U. (2001), Dtsch Med Wochenschr 126(3): 63-4. |
| Disturbed cholesterol homeostasis in a peroxisome-deficient PEX2 knockout mouse model Kovacs, W. J., J. E. Shackelford, et al. (2004), Mol Cell Biol 24(1): 1-13. Abstract: We evaluated the major pathways of cholesterol regulation in the peroxisome-deficient PEX2(-/-) mouse, a model for Zellweger syndrome. Zellweger syndrome is a lethal inherited disorder characterized by severe defects in peroxisome biogenesis and peroxisomal protein import. Compared with wild-type mice, PEX2(-/-) mice have decreased total and high-density lipoprotein cholesterol levels in plasma. Hepatic expression of the SREBP-2 gene is increased 2.5-fold in PEX2(-/-) mice and is associated with increased activities and increased protein and expression levels of SREBP-2-regulated cholesterol biosynthetic enzymes. However, the upregulated cholesterogenic enzymes appear to function with altered efficiency, associated with the loss of peroxisomal compartmentalization. The rate of cholesterol biosynthesis in 7- to 9-day-old PEX2(-/-) mice is markedly increased in most tissues, except in the brain and kidneys, where it is reduced. While the cholesterol content of most tissues is normal in PEX2(-/-) mice, in the knockout mouse liver it is decreased by 40% relative to that in control mice. The classic pathway of bile acid biosynthesis is downregulated in PEX2(-/-) mice. However, expression of CYP27A1, the rate-determining enzyme in the alternate pathway of bile acid synthesis, is upregulated threefold in the PEX2(-/-) mouse liver. The expression of hepatic ATP-binding cassette (ABC) transporters (ABCA1 and ABCG1) involved in cholesterol efflux is not affected in PEX2(-/-) mice. These data illustrate the diversity in cholesterol regulatory responses among different organs in postnatal peroxisome-deficient mice and demonstrate that peroxisomes are critical for maintaining cholesterol homeostasis in the neonatal mouse. |
| Disturbed cholesterol traffic but normal proteolytic function in LAMP-1/LAMP-2 double-deficient fibroblasts Eskelinen, E. L., C. K. Schmidt, et al. (2004), Mol Biol Cell 15(7): 3132-45. Abstract: Mice double deficient in LAMP-1 and -2 were generated. The embryos died between embryonic days 14.5 and 16.5. An accumulation of autophagic vacuoles was detected in many tissues including endothelial cells and Schwann cells. Fibroblast cell lines derived from the double-deficient embryos accumulated autophagic vacuoles and the autophagy protein LC3II after amino acid starvation. Lysosomal vesicles were larger and more peripherally distributed and showed a lower specific density in Percoll gradients in double deficient when compared with control cells. Lysosomal enzyme activities, cathepsin D processing and mannose-6-phosphate receptor expression levels were not affected by the deficiency of both LAMPs. Surprisingly, LAMP-1 and -2 deficiencies did not affect long-lived protein degradation rates, including proteolysis due to chaperone-mediated autophagy. The LAMP-1/2 double-deficient cells and, to a lesser extent, LAMP-2 single-deficient cells showed an accumulation of unesterified cholesterol in endo/lysosomal, rab7, and NPC1 positive compartments as well as reduced amounts of lipid droplets. The cholesterol accumulation in LAMP-1/2 double-deficient cells could be rescued by overexpression of murine LAMP-2a, but not by LAMP-1, highlighting the more prominent role of LAMP-2. Taken together these findings indicate partially overlapping functions for LAMP-1 and -2 in lysosome biogenesis, autophagy, and cholesterol homeostasis. |
| Disturbed regulation of cholesterol synthesis in monocytes of obese patients with hypercholesterolemia Paragh, G., Z. Balogh, et al. (2003), Metabolism 52(1): 1-6. Abstract: The aim of the present study was to clarify the influence of obesity on the functions of low-density lipoprotein receptors (LDL-R) and 3-hydroxy-3-methylglutarate-coenyzme A (HMG-CoA) reductase both in healthy control subjects and in patients with hypercholesterolemia (HC). Experiments were performed on monocytes of 15 non-obese (C I) and 11 obese (C II) healthy control subjects and on 22 non-obese (HC I) and 26 obese (HC II) patients with HC. (125)ILDL was used to determine LDL-R activity by measuring binding and intracellular degradation. The rate of endogenous cholesterol synthesis was measured using (14)Cacetate incorporation into the cholesterol fraction of monocytes. The binding ability of (125)ILDL was identical across all groups. The (14)Cacetate incorporation in resting monocytes was increased only in obese HC group. The 50-microg/mL LDL protein-induced inhibition of (14)Cacetate incorporation was significantly diminished (P <.001) in the same group. A strong positive correlation was detected between the (14)Cacetate incorporation by resting cells and LDL-induced inhibition in all groups except the obese HC group, in which their correlation was negative (P <.001). Furthermore, in the obese HC group, a significant positive correlation was detected between body mass index (BMI) and the basal level of (14)Cacetate incorporation, whereas a negative correlation was found between BMI and LDL-induced inhibition of (14)Cacetate incorporation. The present data suggest that in patients with HC the concomitant obesity results in dysregulation of cholesterol homeostasis, which may contribute to the accelerated atherosclerosis. |
| Diurnal and dietary-induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase Jurevics, H., J. Hostettler, et al. (2000), J Lipid Res 41(7): 1048-54. Abstract: We determined the extent to which diurnal variation in cholesterol synthesis in liver is controlled by steady-state mRNA levels for the rate-limiting enzyme in the pathway, hydroxymethylglutaryl (HMG)-CoA reductase. Rats 30 days of age and maintained on a low-cholesterol diet since weaning were injected intraperitoneally with (3)H(2)O. The specific radioactivity of the whole-body water pool soon became constant, allowing for expression of values for incorporation of label into cholesterol as absolute rates of cholesterol synthesis. In liver, there was a peak of cholesterol synthesis from 8 pm to midnight, a 4-fold increase over synthesis rates from 8 am to noon. Increases in synthesis were quantitatively in lock step with increases in mRNA levels for HMG-CoA reductase occurring 4 h earlier. In a parallel experiment, rats received 1% cholesterol in the diet from weaning to 30 days of age. Basal levels of hepatic cholesterol synthesis were greatly diminished and there was little diurnal variation of cholesterol synthesis or of levels of mRNA for HMG-CoA reductase. Levels of mRNA for the low density lipoprotein receptor and scavenger receptor-B1 (putative high density lipoprotein receptor) showed little diurnal variation, regardless of diet. This suggests that diurnal variation of hepatic cholesterol synthesis is driven primarily by varying the steady-state mRNA levels for HMG-CoA reductase. Other tissues were also examined. Adrenal gland also showed a 4-fold diurnal increase in accumulation of recently synthesized cholesterol. In contrast to liver, however, there was little corresponding change in mRNA expression for HMG-CoA reductase. Much of this newly synthesized cholesterol may be of hepatic origin, imported into adrenal by SR-B1, whose mRNA was up-regulated 2-fold. In brain, there was no diurnal variation in either cholesterol synthesis or mRNA expression, and no influence of high- or low-cholesterol diets on synthesis rates or HMG-CoA reductase mRNA levels. |
| Diurnal rhythm of cholesterol biosynthesis in experimental chronic renal failure Chmielewski, M., T. Nieweglowski, et al. (2001), Mol Cell Biochem 228(1-2): 33-7. Abstract: Changes in lipid metabolism are an important risk factor for vascular complications during chronic renal failure (CRF). In experimental CRF hypercholesterolemia has been found to be the main lipid disorder. It is probably due to enhanced cholesterologenesis. Mechanisms of these changes remain poorly understood. It is well known that activity of cholesterologenesis undergoes a significant diurnal rhythm. However, there was no evidence that this rhythm is still present in the course of experimental CRF. Results of our studies indicate that in contrast to puromycin induced nephrotic syndrome, diurnal rhythm of cholesterologenesis in CRF rats is preserved both in liver and in the intestine tissue. Significant higher incorporation of tritiated water into cholesterol fraction was found in vivo both in liver as well as in intestine of CRF rats, as compared to control animals. Increased (with comparison to the controls) incorporation of 14C-acetate, and 3H-mevalonate into CRF rat liver sterols indicate that mechanism of enhanced cholesterologenesis is more complex than simply due to the elevated level of mevalonate (potential substrate for cholesterologenesis) which has been reported in plasma of CRF animals. |
| Diurnal rhythmicity of human cholesterol synthesis: normal pattern and adaptation to simulated "jet lag" Cella, L. K., E. Van Cauter, et al. (1995), Am J Physiol 269(3 Pt 1): E489-98. Abstract: The diurnal rhythm of cholesterol synthesis was determined by deuterium incorporation from body water in five normolipemic men studied during a 24-h baseline period and on the 1st, 2nd, and 4th days of a simulated 12-h time zone shift achieved by delaying sleep times and, starting on the 2nd day, meal-times. Profiles of plasma cortisol and thyrotropin (TSH) were obtained simultaneously. Under baseline conditions, cholesterol synthetic rates varied from essentially zero in the morning to maximal values around midnight. On the 1st shifted day, this diurnal variation was unaltered despite sleep-wake reversal. The diurnal pattern of cholesterol synthesis, however, was shifted 5 h on the 2nd shifted day and approximately 12 h on the 4th. The diurnal variation of synthetic rate cholesterol fractional synthesis and plasma cortisol levels was negatively correlated on both the baseline day and the 1st shifted day. A positive correlation with the TSH rhythm was found on the 1st day only. During the 2nd and 4th days, the rhythm of cholesterol synthesis adapted faster than the rhythms of cortisol and TSH. These findings indicate that cholesterol synthesis is not acutely entrained by the sleep-wake cycle nor is it primarily entrained by the circadian clock. |
| Diurnal variation in cholesterol metastability of hepatic bile and its acute modulation with ursodeoxycholic acid in humans Noshiro, H., K. Chijiiwa, et al. (1992), J Hepatol 16(1-2): 23-30. Abstract: We studied the alteration of cholesterol metastability of hepatic bile caused by diurnal variations in hepatic biliary lipid excretions and acutely induced changes following ursodeoxycholic acid (UCDA) administration. Hepatic bile was collected at 6-h intervals for 24 h from 6 patients with an indwelling choledochal drainage before and after UDCA administration. A basal diurnal variation showed the highest cholesterol saturation index (p < 0.05) and cholesterol distribution in vesicles (p < 0.01) and the shortest nucleation time (p < 0.05) in the early morning. After the ingestion of ursodeoxycholic acid for 1 day, early morning biliary cholesterol concentrations were reduced. Interestingly, significant decreases in vesicular cholesterol concentrations (1.0 +/- 0.2 to 0.1 +/- 0.04 mM, p < 0.01) and in the vesicular cholesterol/phospholipid ratio (1.6 +/- 0.1 to 0.7 +/- 0.1, p < 0.05) were associated with prolongation of the nucleation time (11.5 +/- 1.2 to 18.7 +/- 1.5 days, p < 0.01). Biliary protein had no diurnal variations and did not decrease significantly with UCDA. These results indicate that during a day the early morning hepatic bile is the most unstable and that UCDA acutely enhances hepatic biliary metastability mainly by decreasing the rate of vesicular cholesterol saturation. |
| Diurnal variations of rat liver enzymes catalyzing cholesterol ester hydrolysis Martinez, M. J., J. I. Ruiz, et al. (1991), Biochim Biophys Acta 1085(1): 106-11. Abstract: Cholesterol ester hydrolase activity was determined at 3 h time intervals over 24 h in lysosomes, cytosol and microsomes from ad libitum-fed and 24 h food-deprived female rat liver. Diurnal rhythms were identified for the acid and neutral esterases, which were strikingly changed by fasting. In fed animals, lysosomal esterase specific activity exhibited a peak at noon and a sustained medium rate at early darkness, whereas total esterase was maximal at midnight. The circadian patterns of the cytosolic and the microsomal esterases paralleled each other, though the amplitude of rhythms differed, showing higher activities around midnight. After fasting, cholesterol esterase activity from all cell fractions reached a maximum near dark onset. These results are the first to indicate that cholesteryl ester hydrolysis may play a role in generating the diurnal rhythm of hepatic cholesterol. |
| Divergent age-associated patterns of high density lipoprotein cholesterol and its percentage in Jewish and Moslem Arab Israeli children and adolescents: the Petach Tikva Project Greenland, P., U. Goldbourt, et al. (1993), Am J Epidemiol 137(5): 549-58. Abstract: We studied three groups of Israeli Jewish schoolchildren in and surrounding Petach Tikva, Israel, cross-sectionally, at ages 9-10, 13-14, and 16-18 years, and compared lipid and lipoprotein levels and age-associated lipoprotein patterns in the same age groups of boys and girls in neighboring Israeli Moslem Arab schools during 1986-1987. Moslem children displayed striking differences in the levels of lipids and age-associated patterns of lipoproteins compared with Jewish schoolchildren. The mean total cholesterol levels were lower in the Moslem children, in both sexes, in every age grouping. High density lipoprotein cholesterol (HDL-C) levels were significantly higher at age 16-18 in the Moslem boys than in the Jewish boys. While the Jewish boys displayed a previously reported "typical" pattern of lower HDL-C levels postpuberty compared with prepuberty, the Moslem boys had markedly higher mean HDL-C levels at age 16-18 compared with those at age 9-10. The Moslem girls also had higher HDL-C levels at age 16-18 than those observed in the age 9-10 group. Concomitantly higher HDL-C levels (HDL-C/total cholesterol (%)) were seen in the Moslem boys and girls, at age 16-18 compared with age 9-10, but were not observed in the Jewish children. The identification of an ethnic group in whom HDL-C appears to increase at or near puberty could provide opportunities to elucidate factors that may increase HDL-C in individuals or in populations. |
| Divergent approaches to the treatment of dyslipidemia with low levels of high-density lipoprotein cholesterol Pearson, T. A. (2000), Am J Cardiol 86(12A): 57L-61L. Abstract: Further therapy should be considered for patients who have reached target low-density lipoprotein cholesterol (LDL-C) levels but have low plasma levels of high-density lipoprotein cholesterol (HDL-C) since rates of coronary artery disease continue to be high for a sizable proportion of this population. Lifestyle approaches include dietary changes, smoking cessation, moderate alcohol intake, concomitant drug reassessment, and specific coexistent conditions. Aggressive statin therapy still leaves a high residual rate of cardiac events. Other drug approaches include estrogen, fibrate, niacin therapy, and combinations of these agents. Recent results from an ongoing trial of combination extended-release prescription niacin plus lovastatin are very promising. |
| Divergent concentrations of plasma metabolites in swine selected for seven generations for high or low plasma total cholesterol Pond, W. G., D. R. Su, et al. (1997), J Anim Sci 75(2): 311-6. Abstract: It was reported previously that selection for high (HG) or low (LG) plasma total cholesterol (TC) at 8 wk of age in a composite four-breed swine population resulted after four generations in divergent mean concentrations in the selected lines. The data revealed a significant positive correlation between body weight (BW) and TC concentration at 8 wk of age and differential responses in litter size, backfat depth, and carcass length at 6 mo of age. We report here the relationship between plasma TC concentration and other plasma traits related to growth and metabolism in the seventh generation of selection in these two lines of pigs. We measured plasma concentrations of TC, HDL cholesterol (HDL-C), triglycerides (TG), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), urea nitrogen (urea N), and three transaminases (alanine aminotransferase, ALT; aspartate aminotransferase, AST; gamma glutamyltransferase, GGT) in seventh-generation male and female pigs at 8 wk of age. Birth weight (1.48 vs 1.38 kg), 8 wk BW (14.85 vs 12.00 kg), TC (116.8 vs 63.6 mg/dL), HDL-C (43.9 vs 25.5 mg/dL), TG (50.5 vs 33.0 mg/dL), and ALP (78.3 vs 44.9 units/L) were higher (P <.01) in HG than in LG pigs, whereas ALB (3.2 vs 3.4 g/dL), ALT (43.0 vs 45.9 units/L), and AST (53.0 vs 62.2 units/L) were lower in HG than in LG pigs (P <.05). At 8 wk, overall plasma TC concentration was correlated with BW (r =.34, P <.01) and with ALP (r =.23, P <.05) but was not related to ALT, AST, or GGT. Plasma TP urea N, and GGT were unaffected by genetic line on sex. We conclude that the difference between HG and LG pigs in TC concentration in generation 4 at 8 wk of age has persisted but not broadened in pigs of generation 7, that changes in plasma ALP, ALT, and AST may have occurred in response to selection for high or low plasma TC, and that ALP is correlated with plasma TC concentration. |
| Divergent pharmacologic activities of PD 132301-2 and CL 277,082, urea inhibitors of acyl-CoA:cholesterol acyltransferase Krause, B. R., A. Black, et al. (1993), J Pharmacol Exp Ther 267(2): 734-43. Abstract: The in vitro potencies and hypocholesterolemic properties of CL 277,082 and PD 132301-2, two urea inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) were compared. PD 132301-2 was several-fold more potent at inhibiting ACAT in microsomes from rat and rabbit tissues and in cultured cells (murine macrophages and the human HepG2 cell line). This disubstituted urea was also relatively specific for ACAT as other cholesterol esterifying enzymes (e.g., lecithin:cholesterol acyltransferase, pancreatic cholesterol ester hydrolase), as well as intestinal diglyceride synthesis (acyl-CoA:monoglyceride acyltransferase), were unaffected in vitro at relevant concentrations. In normal chow-fed rats, both compounds reduced plasma triglycerides at doses > 50 mg/kg, but only PD 132301-2 reduced plasma cholesterol. In rat and rabbit models of hypercholesterolemia the greater in vitro potency of PD 132301-2 translated into greater in vivo efficacy (i.e., ED50 values 2- to 3-fold higher for CL 277,082 in both acute and chronic rate models). Of particular note was the greater elevation of high-density lipoprotein-cholesterol and parenteral activity of PD 132301-2 compared to CL 277,082 in the chronic rat model. Inhibition of cholesterol absorption in rats was also greater with PD 132301-2. In guinea pigs, in which 77% of plasma cholesterol was transported in low-density lipoprotein, PD 132301-2 potently reduced plasma total cholesterol (lowest significant dose = 1 mg/kg) as well as plasma triglycerides. CL 277,082 only reduced cholesterol at doses > 100 mg/kg in this low-density lipoprotein model. In a canine model of hypercholesterolemia CL 277,082 was inactive at doses up to 50 mg/kg, but PD 132301-2 was active at 3 mg/kg. Moreover, efficacy in dogs with PD 132301-2 was positively correlated with plasma drug concentration, an observation not previously demonstrated for other hypolipidemic drugs. The combined data illustrate that pharmacologic activities can vary widely among ACAT inhibitors of the same general class. In addition, the unique observation of proportionality between efficacy and blood drug levels in nonrodent animal models may not only help to simplify early stages in drug development but also may help to predict or monitor a direct action of the drug on vascular disease. |
| DNA polymorphisms of the apolipoprotein AI/CIII/AIV gene cluster influence plasma cholesterol and triglyceride levels in the Mayans of the Yucatan Peninsula, Mexico Ahn, Y. I., R. Valdez, et al. (1991), Hum Hered 41(5): 281-9. Abstract: The purpose of this work was to examine the influence of apolipoprotein gene variation on plasma lipid levels in a population of Mayan Indians of the Yucatan Peninsula, Mexico. Four restriction enzymes: XmnI, PstI, SstI, and PvuII, were used to detect restriction fragment length polymorphisms (RFLP) within the region of the apolipoprotein AI/CIII/AIV gene cluster. The frequencies of these polymorphisms in this Mayan population were similar to those reported for other Amerindian populations, but differed widely from those reported for Caucasian populations. The XmnI and SstI RFLPs were informative for association studies in this population, and we analyzed their influence on the quantitative variation of plasma cholesterol and triglycerides. Using a nonparametric analysis of variance, it is shown that the presence of the XmnI restriction site had a significant effect in lowering plasma cholesterol, whereas the presence of the restriction site for SstI had a significant effect in raising plasma triglycerides. Consequently, genetic indicators of both low and high risk for lipid-related diseases, such as atherosclerosis and coronary heart disease, seem to be present within the same gene region in this Mayan population. |