Normal Plasma Cholesterol Levels Research Articles

Synthesis of 3-ureido derivatives of coumarin and 2-quinolone as potent acyl-CoA: cholesterol acyltransferase inhibitors.

Novel 3-ureido derivatives of 4-phenylcoumarin and 4-phenyl-2-quinolone were synthesized and evaluated for acyl-CoA: cholesterol acyltransferase (ACAT)-inhibitory activity. These derivatives inhibited rat intestinal ACAT with IC50 values at the 10(-8) to 10(-9) M level and were found to normalize plasma cholesterol levels in cholesterol-fed rats when administered as dietary admixtures.

Cholesterol and cholesterol sulphate concentration in the cell membrane complex of human scalp hair — A biomarker of aging?

Cell to cell cohesion in fully keratinized hair is mediated by a cell membrane complex which contains covalently bound (integral) hair lipids. The influence of aging on concentrations of integral cholesterol sulphate (CHSU) and cholesterol (CH) in human scalp hair shafts, and the relationship between hair and plasma lipids were examined in 50 subjects, aged 18 to 87 years, and in one case of Werner's syndrome. Hair CHSU concentrations were distributed normally and were significantly higher in male subjects with elevated plasma CH levels (>5.17 mmol/l) than in those with normal plasma CH levels (806+/-134 versus 624+/-155 nmol/g hair, p<0.001). Female subjects with elevated plasma CH levels had even lower hair CHSU, values (515+/-167 nmol/g hair, p<0.05) than men with normal plasma CH. The almost white hairs of the Werner's syndrome patient displayed low levels of CHSU, possibly indicating a precarious hair stability. A small but statistically significant linear correlation between donor age and integral CH in hair (n=51; y=97.7+0.9x; cc=0.32; p<0.05) was detected. No correlation between hair CHSU and age could be demonstrated. Since internal hair lipid concentrations do not correlate with plasma lipids, the age associated increase of hair CH as well as the observed gender differences in hair CHSU concentration may be related to alterations in the process of keratinization. Hair CH analysis seems to be of little significance in the clinical diagnosis of hypercholesterolemia.

Enhanced Low-Density Lipoprotein Degradation and Cholesterol Synthesis in Monocyte-Derived Macrophages of Patients with Adult Xanthogranulomatosis

Adult xanthogranulomatosis is an uncommon disorder in which dermal macrophages accumulate cholesterol intracellularly despite normal plasma cholesterol levels. In an attempt to elucidate an underlying biochemical abnormality in this disorder, we studied the rates of 125I-labeled low-density lipoprotein degradation, and intracellular cholesterol synthesis, in human monocyte-derived macrophages of three patients with adult xanthogranulomatosis. In all three patients, the rates of cellular 125I-low-density lipoprotein degradation and of cholesterol synthesis were 22-37% and 14-84% higher than those of the respective normal controls (p < 0.01). These findings suggest that in MDM of adult xanthogranulomatosis patients, the uptake and degradation of low-density lipoprotein-derived cholesterol and intracellular cholesterol biosynthesis are enhanced. Because dermal macrophages are derived from blood monocytes, it is possible that such an enhancement might play a role in the accumulation of cholesteryl esters in the macrophages that form the xanthogranulomatosis lesions.

Reduced HDL2 cholesterol subspecies and elevated postheparin hepatic lipase activity in older men with abdominal obesity and asymptomatic myocardial ischemia.

Silent myocardial ischemia (SI), an asymptomatic manifestation of coronary artery disease (CAD), was identified in 10% of apparently healthy nonsmoking, nondiabetic older (60 +/- 7 years, mean +/- SD) men with normal plasma cholesterol levels. We hypothesized that in the absence of other major risk factors for CAD, the men with SI would have reduced plasma levels of high density lipoprotein (HDL) and HDL2 subspecies due to an upper-body fat distribution (waist-to-hip ratio [WHR]), hyperinsulinemia, and abnormal postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities. Compared with 47 normal control subjects of similar age, obesity, and maximal aerobic capacity, the 18 men with SI had higher plasma triglyceride (TG) (162 +/- 71 versus 102 +/- 39 mg/dl, p less than 0.001) and lower HDL-C (33 +/- 6 versus 37 +/- 7 mg/dl, p less than 0.02) levels with no difference in low density lipoprotein cholesterol level. The HDL2b and HDL2a subspecies measured by gradient gel electrophoresis were also lower in the men with SI (p less than 0.01). The plasma glucose and insulin responses during an oral glucose tolerance test were the same in both groups. Postheparin plasma HL activity was significantly higher in 12 men with SI than in 41 control subjects (34 +/- 8 versus 27 +/- 10 mumol/ml.hr-1, p less than 0.03) and was correlated with log insulin area (r = 0.36, p less than 0.05) and WHR (r = 0.32, p less than 0.05) in the control subjects but not in the men with SI. In the control group, the percent HDL2b subspecies was correlated inversely with postheparin plasma HL activity (r = -0.46, p less than 0.01, n = 41) as well as WHR (r = -0.49, p less than 0.001, n = 47) and log insulin area (r = -0.37, p less than 0.05, n = 47) but not in the men with SI. Postheparin LPL activity was the same in both groups of men and did not correlate with HDL, WHR, insulin, or plasma TG levels. As the control subjects and men with SI had comparable degrees of abdominal obesity and hyperinsulinemia, these results suggest that the reduced HDL-C levels in men with SI may be related to elevations in HL activity. Thus, abdominal obesity, hyperinsulinemia, elevated TG levels, and low HDL-C and HDL2 subspecies levels may predispose these older men to atherosclerosis.

Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: The cholesterol and recurrent events trial (CARE)

Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol. However, it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited. Several previous prevention trials reviewed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range (e.g., >240 mg/dl) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline. The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed. The Cholesterol and Recurrent Events trial is testing whether pravastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, will decrease the sum of fatal coronary heart disease and nonfatal myocardial infarction (MI) in patients who have recovered from a MI and who have normal total cholesterol levels. Fatal cardiovascular disease and total mortality are important secondary end points. The trial is enrolling 4,000 men and women from 80 centers throughout North America, age 21 to 75 years, who have survived MI for 3 to 20 months, who have plasma total cholesterol <240 mg/dl (6.2 mmol/ liter) and low-density cholesterol of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter), and who are representative of the general population of patients with MI. Patients are randomized to either active or inactive drug therapy. Active therapy consists of pravastatin, 40 mg/day, designed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30%, and an increase in high-density lipoprotein of 5%. The average duration of follow-up will be ≥5 years. To protect against a lower than expected rate of recurrent events, the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained.

Coinheritance of Two Mild Defects in Low Density Lipoprotein Receptor Function Produces Severe Hypercholesterolemia*

A family is described in which the probands, twin girls, had severe hypercholesterolemia suggestive of familial hypercholesterolemia (FH). The mother of the twins had normal plasma cholesterol levels, and the father had only moderate hypercholesterolemia. Moreover, low density lipoprotein (LDL) binding studies in cultured fibroblasts and isolated lymphocytes in the parents failed to reveal significantly reduced LDL receptor activity that is typical of FH heterozygotes. Turnover studies of LDL in the parents, however, revealed low fractional clearance rates (FCRs) for LDL. In cultured fibroblasts and isolated lymphocytes from the twin probands, binding of normal LDL was half normal or less. LDL turnover studies in the twins revealed a marked reduction in FCRs for LDL. When the twins were treated with lovastatin, however, FCRs for LDL increased significantly, suggesting enhancement of LDL receptor activity. This finding along with LDL binding studies in the cultured cells infer that the twins did not have homozygous FH. In addition, all family members tested negative for familial defective apolipoprotein-B-100, and LDL isolated from the mother and twins showed normal binding to normal fibroblasts. The overall data suggest that the severe hypercholesterolemia in the offspring was due to inheritance of mild to moderate defects of LDL receptor function from both parents. Although the latter defects could not be detected with certainty by in vitro tests in each parent, they were evident from LDL turnover tests. Coinheritance of these defects apparently produced severe hypercholesterolemia in the offspring.

Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders

Patients with myeloproliferative disorders demonstrate decreased plasma cholesterol and apolipoprotein B concentrations, and this has been related to the presence of a large spleen. Patients that underwent splenectomy in the past demonstrated normal plasma cholesterol levels. Plasma high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were also reduced in these patients, but were normal after splenectomy. To study the immediate effect of splenectomy on the plasma lipid pattern, three patients with myeloproliferative disease and a large spleen who were undergoing splenectomy were compared with two control groups, one undergoing orthopedic operations and the second, cholecystectomy. In the control groups, plasma lipids tended to decrease for the first 2 days after surgery and then returned to preoperative levels. After splenectomy, however, plasma cholesterol, low-density lipoprotein (LDL), and apolipoprotein B significantly increased, reaching maximum levels after 4 days. Plasma HDL as well as apolipoprotein A-I decreased 1 day after splenectomy, but then increased over and above their preoperative concentrations. These results suggest an important role for the spleen in cholesterol metabolism in these patients. The spleen appears to be an important site for LDL catabolism in these patients.

Erythrocyte and leukocyte lipids in alcoholic macrocytosis

Erythrocytes and leukocytes were obtained from patients with alcoholic macrocytosis and their lipid composition compared with those from normal subjects. The patients had normal plasma cholesterol and fasting triglyceride levels with mild and fully compensated liver disease. There was no difference in the lipid composition of leukocytes from alcoholics compared with controls. Erythrocytes from patients with alcoholic macrocytosis had increased cholesterol content. The increased cholesterol content correlated with the MCV but there was no correlation between plasma and erythrocyte cholesterol. There was a decrease in erythrocyte phosphatidylethanolamine in alcoholic macrocytosis. There was no change in the fatty acid composition of the phospholipid fraction but there was an increase in the amount of linoleic acid in phosphatidylethanolamine. The double bond index, non-essential-to-essential fatty acid ratio and double bond index to saturated fatty acid ratio for the erythrocyte phospholipids were unchanged in alcoholic macrocytosis. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of erythrocyte membrane proteins from patients with alcoholic macrocytosis and control subjects showed no significant differences.

Identification of 5 alpha-stanols in patients with sitosterolemia and xanthomatosis: stereochemistry of the protonolysis of steroidal organoboranes.

Plasma and fecal sterols of patients who exhibited tendon xanthomas with normal plasma cholesterol levels were studied. Plasma levels were (mg/dl mean +/- SD): cholesterol 232 +/- 36; cholestanol 5.9 +/- 2.1 (normal less than 0.6); sitosterol 18 +/- 5.6 (normal less than 1.0); campesterol 11 +/- 3.3 (normal less than 1.0). Other sterols such as sitostanol and campestanol (the 5 alpha-dihydro derivatives of sitosterol and campesterol) were also present in large amounts. Examination of the feces from these subjects showed cholesterol, sitosterol, campesterol and their 5 beta-saturated derivatives. Presence of 5 alpha-stanols in the plasma, and their absence in the feces indicates that the 5 alpha-stanols are synthesized endogenously within the body rather than in the intestine by colonic bacteria. The absolute identification of the structures of these 5 alpha-stanols was elucidated via hydroboration of their corresponding unsaturated sterols coupled with protonolysis of the resultant organoboranes.

In vivo chemotaxis of rat leukocytes in the presence of circulating chylomicrons

Dietary-induced chylomicronemia was produced in rats to determine its effect on the chemotactic activity of 51Cr-labelled adoptively transferred isologous leukocytes. Rats fed a low protein high fat diet for 2 months had normal total plasma cholesterol and triglyceride levels, but increased amounts of chylomicrons. Circulating neutrophils and monocytes from animals on a normal diet were able to phagocytose chylomicrons from plasma of those animals on the special diet. Peritoneal exudate cells from the latter animals contained intracellular chylomicrons demonstratable both histologically and biochemically. Neutrophils and mononuclear cells from normal or special fed animals, when transferred to chylomicronemic recipients, had a reduced ability to accumulate at the site of a complement-dependent inflammatory reaction but circulated normally. The defective chemotactic activity observed could be duplicated when cells were allowed to ingest aggregated protein instead of chylomicrons. It was concluded that circulating leukocytes ingest chylomicrons from the plasma with a resultant reduction in their chemotactic activity. The results were discussed in relation to the increased incidence of infection in diabetes characterized by Type I and V hyperlipidemias. It was also suggested that phagocytosis of particulate substances by entrapped leukocytes in atherosclerotic lesions would induce phagocytic enzyme release which could contribute to the eventual destruction of the vascular wall.

β-Sitosterolemia and Xanthomatosis

Although the usual diet may contain 150-250 mg of plant sterols, chiefly beta-sitosterol, only trace amounts of these sterols have heretofore been found in human or animal blood and tissues. We now report elevated plant sterol levels in the blood and tissues of two sisters with extensive tendon xanthomas but normal plasma cholesterol levels. Besides beta-sitosterolemia and xanthomatosis, no other physical, mental, or biochemical abnormalities were detected.Repeatedly, the plasmas of the two sisters have contained 27.1 and 17.7 mg/100 ml of beta-sitosterol, 9.7 and 8.2 mg/100 ml of campesterol, and 0.5 and 0.5 mg/100 ml of stigmasterol, respectively. These plant sterols constituted 15.6 and 11.3% of the total plasma sterols. Some 60% of the plasma beta-sitosterol and campesterol was esterified; the measurable stigmasterol was entirely unesterified. The transport of the plasma beta-sitosterol and campesterol was largely in low density lipoproteins (76 and 83%, respectively). High density lipoproteins carried the remainder. Plant sterols were barely detectable in the very low density lipoprotein fraction. Only trace amounts of stigmasterol could be detected in the low density and high density lipoprotein fractions. The plant sterol content of the red blood cells averaged 12-13 mg/100 ml packed cells or about 13% of the total sterols. Two tendon xanthoma biopsies with the usual high concentration of cholesterol had 36.7 and 4.0 mg of plant sterols/g dry wt, of which 25.7 and 2.9 mg were beta-sitosterol, entirely in the free form. Plant sterols were also found in adipose tissue (0.2 mg/g wet wt) and in skin surface lipids (3.2 mg/g of lipid). The intestinal absorption of beta-sitosterol in both the patients, measured by two techniques, indicated greatly increased absorption of this sterol (about 24 and 28% in the patients L. H. and R. H., respectively, normal absorption being <5%). We suggest that increased absorption of beta-sitosterol must be considered as one cause of this disease. The reason for the extensive xanthomatosis in these two patients remains unknown. Perhaps in some way plant sterols initiated the development of xanthomas with otherwise normal plasma cholesterol levels. Clinical atherosclerosis has not yet occurred. The occurrence of beta-sitosterolemia in these two sisters with un-affected parents suggests an inherited recessive trait.

Cord blood hypertriglyceridemia.

Cord blood triglyceride (TG) concentrations were determined in 60 neonates whose parents had normal plasma cholesterol and triglyceride levels, and in 57 neonates with one parent having primary hypertriglyceridemia. The 95th percentile value for cord blood triglyceride in both groups of neonates was 70 mg/100 ml, and this level was arbitrarily used as a cutoff point in the definition of cord blood hypertriglyceridemia. In 2,000 consecutive live births, 56 neonates had cord blood triglyceride levels > 70 mg/100 ml (mean TG 111±33, range 71 to 218 mg/100 ml). Forty-six neonates with triglyceride levels

Hypophagia, hypodipsia and hypoactivity following dorsomedial hypothalamic lesions

Bilateral electrolytic lesions in the dorsomedial hypothalamic nuclei (DMNL) of the weanling male rat resulted in hypophagia and hypodipsia, reduced ponderal and linear growth, reduced spontaneous activity, normal carcass fat and increased carcass protein. Previous data in DMNL rats show normal plasma growth hormone, insulin, glucose, cholesterol and triglyceride levels. In the present study, thyroid and testes weights were normal and the reduced metabolic rate is likely due to the profound hypophagia. This makes it unlikely that the poor growth in these animals is due to neuroendocrine disturbances. Rather, it appears to be the result of hypocaloric food intake. Whether the latter is due to a motor failure or a motivational deficit is not established by the present data. The DMN area responsible for the above syndrome is either a primary activity center or a thoroughfare for pathways from other such centers located else-where in the hypothalamus.