Normal Plasma Cholesterol Research Articles

Different Substrate Specificities of Plasma Lecithin: Cholesterol Acyl Transferase in Fish Eye Disease and Tangier Disease

Esterification of plasma free cholesterol is mediated by lecithin:cholesterol acyl transferase (LCAT). The free cholesterol of plasma high density lipoproteins (HDL) is considered to be the preferred substrate for LCAT. It therefore appeared as a paradox that plasma cholesterol esterification, both in vivo and in vitro, is normal in fish eye disease and Tangier disease, two familial conditions with extremely low plasma HDL levels. Fish eye disease plasma, however, was shown to have LCAT activity primarily acting on combined very low (VLDL) and low (LDL) density lipoproteins, denominated beta-LCAT, while it lacked LCAT activity esterifying HDL cholesterol (alpha-LCAT). Here we show that Tangier plasma, in contrast, has both alpha- and beta-LCAT. Thus, in both fish eye and Tangier diseases it is beta-LCAT that explains the apparent normal plasma cholesterol esterification. We also show that Tangier plasma, having alpha-LCAT activity, normalizes the low cholesteryl ester content as well as the abnormally small size of fish eye disease HDL particles during incubation.

Dietary protein effects on cholesterol and lipoprotein concentrations: a review.

Different dietary proteins exert different effects on plasma cholesterol concentrations. Animal studies have shown that animal proteins, most notably casein, increase plasma total cholesterol concentrations compared with vegetable proteins, such as soy. Soy protein has been shown to be hypocholesterolemic in rats, swine, primates, and rabbits. Epidemiologic studies have disclosed that vegetarians have lower mean plasma cholesterol concentrations than populations consuming diets of mixed proteins, but it is unclear whether this effect results specifically from the animal or vegetable nature of the protein. In human clinical experiments, substituting soy protein for mixed protein reduces plasma total cholesterol concentration in hypercholesterolemic subjects, but it causes only a small, nonsignificant change in persons with normal plasma cholesterol concentrations. The mechanism responsible for the effects of different proteins on plasma cholesterol concentrations has not been established. One hypothesis suggests that animal proteins, which have a greater content of phosphorylated amino acids than vegetable proteins, interfere with bile acid reabsorption. Another hypothesis suggests that the amino acid content of the protein affects cholesterol absorption, tissue storage, synthesis, and excretion. The dietary protein may also alter cholesterol metabolism by affecting plasma hormone concentrations, either postprandially or over weeks to months. Among the hormones thought to be affected by dietary protein source are insulin, glucagon, and thyroid hormones. Gastrointestinal hormones, such as gastrointestinal inhibitory polypeptide, may also be affected by dietary protein.

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.

Treatment of homozygous familial hypercholesterolaemia: an informative sibship.

In a family in which both parents had the heterozygous form of familial hypercholesterolaemia four of the children had the homozygous form. The three oldest homozygous children, two of whom did not receive any treatment and in one of whom treatment did not lower the plasma cholesterol concentration, developed xanthomas in early childhood and died aged 3, 9, and 10 years. The fourth homozygous child was treated with diet and drugs from the age of 1 and at the age of 15 had no xanthomas, no clinical evidence of heart disease, and a virtually normal coronary angiogram. His plasma cholesterol concentration was reduced by about 30% but remained considerably raised. It is concluded that treatment, if started before atherosclerosis develops, can delay the onset of atheroma and coronary heart disease even though normal plasma cholesterol concentrations are not achieved.

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.

Cholesterol exchange in platelets, erythrocytes and megakaryocytes

Cholesterol exchange between plasma and human platelets and erythrocytes and guinea pig platelets, erythrocytes and megakaryocytes was studied. The characteristics of exchange of cholesterol between [ 3H]cholesterol-labeled plasma and human platelets and erythrocytes were similar: exchange per cell was independent of cell concentration in whole plasma, decreased only 2-fold over a wide range of cell concentrations in low concentrations of plasma and approached a plateau at 1/3 normal plasma cholesterol concentration, and there was no net change in the cholesterol content of either cell. The activation energy for exchange for both cells was 47 kJ/mol. In all experiments, erythrocyte cholesterol was labeled to approximately twice the specific activity of platelet cholesterol. Guinea pig megakaryocyte cholesterol exchanged at 25–33% of the rate of guinea pig platelet cholesterol in vitro. Similarly, when guinea pigs were fed [ 3H]cholesterol], erythrocyte cholesterol specific activity after 24 h was 90%, platelet 50–65%, and megakaryocyte 20–26% that of plasma. Guinea pig platelets incubated with plasma radiolabeled in free and esterified cholesterol incorporated radioactivity from free but not esterified cholesterol. The similarity of free cholesterol exchange in platelets and erythrocytes in vitro and in vivo and the apparent inability of platelets to take up cholesterol esters from lipoproteins suggest that the interaction between normal platelets and normocholesterolemic plasma is limited to cholesterol exchange.

Apolipoprotein E phenotypes in patients with myocardial infarction.

The frequencies of genetic apo E isoforms E2, E3 and E4 were determined in 523 patients with myocardial infarction and compared to those in a control group (1031 blood donors). A significant difference in the frequency of apo E4 was noted between patients and controls (0.05 greater than P greater than 0.025). No differences in the frequencies of isoforms E3 and E2 were observed. In particular, there was no significant difference between the two groups in the frequency of apo E2 homozygosity, a condition that is associated with type III hyperlipoproteinemia. However, all E2 homozygote survivors of myocardial infarction had hyperlipoproteinemia type III (cholesterol 269 +/- 29 mg/dl; triglyceride 419 +/- 150 mg/dl; age 54 +/- 14 years; N = 5). On the contrary, E2 homozygote controls (all apo E-2/2 blood donors and their apo E-2/2 relatives who were from the same age range as the patients) had primary dysbetalipoproteinemia but normal or subnormal plasma cholesterol concentrations (cholesterol 184 +/- 28 mg/dl; triglyceride 151 +/- 52 mg/dl; age 56 +/- 13 years; N = 11). This indicates that E2 homozygotes with hyperlipoproteinemia type III who occur rarely in the population but comprise about 1% of myocardial infarction patients have a markedly increased risk for coronary atherosclerosis, whereas the risk for E2 homozygotes with normal or subnormal plasma cholesterol (= primary dysbetalipoproteinemia) may be considerably lower than for the general population. The data illustrate the complex relationship between apo E genes, lipid levels, and risk for atherosclerosis.

The influence of continuous ambulatory peritoneal dialysis on plasma lipoproteins

A number of patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis (CAPD) develop hypertriglyceridemia. In order to assess the extent of lipoprotein complications and possible mechanisms, we studied the plasma lipoprotein levels in relation to the duration of treatment with CAPD and lipoprotein removal by the peritoneal dialysis solution.Plasma lipoprotein levels were investigated at the start of CAPD and after 3–6 months of treatment. The patients were divided into the following groups: Group I, 13 non-diabetic patients with normal plasma levels of cholesterol and triglycerides at the start of the treatment; Group 11, 8 non-diabetic patients with established hypertriglyceridemia at the beginning of the treatment; and Group 111, 7 patients with diabetic end-stage renal disease. Patients of Group I showed a significant (P < 0.01) increase in HDL cholesterol (32.2 ± 8.4 to 42.8 ± 10.6 mg/dl) during treatment. In contrast, HDL concentrations showed no significant change in Group II (34.0 ± 5.5 to 30.9 ± 5.8 mg/dl) or Group III (37.0 ± 10.2 to 39.3 – 10.3 mg/dl). The other lipoproteins showed no significant trends. It is concluded that CAPD is associated with an increase in HDL cholesterol in non-diabetics who at the beginning of the treatment have normal plasma cholesterol and triglycerides. In contrast non-diabetics with hypertriglyceridemia and diabetics on CAPD show no significant changes in their plasma HDL cholesterol concentration.The dialysis solution, which was left in the peritoneal cavity for 6 h, contained both low and high density lipoproteins. Apolipoproteins A-I, A-II, C-II, C-III and B were detected in high density and low density lipoproteins. However, apolipoproteins were not detected in the ultracentrifugal infranatant after centrifugation at density = 1.25 g/ml. The rate of loss of lipoprotein cholesterol into the dialysate was 2.6 ± 1.4 mg/h for low density lipoproteins and 1.9 ± 0.8 mg/h for high density lipoproteins. Thus, the loss of lipoprotein in the dialysate was small in relation to the net synthetic rates reported by others for apolipoproteins and could not account for the hypertriglyceridemia.

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 vitro regulation of cholesterol metabolism by low density lipoproteins in skin fibroblasts from hypo- and hyperresponding squirrel monkeys

When squirrel monkeys ( Saimiri sciureus) are fed diets containing cholesterol, some individuals (hyperresponders) become hypercholesterolemic, while others (hyporesponders) are able to maintain nearly normal plasma cholesterol concentrations. Skin fibroblasts were grown from three hyperresponder and three hyporesponder squirrel monkeys, previously characterized on the basis of their plasma cholesterol response to two cholesterol-containing diets and the phenotype of their parents. The rates of cholesterol synthesis and esterification were determined in the cultured fibroblasts incubated with low density lipoproteins isolated from normocholesterolemic squirrel monkeys or hypercholesterolemic rhesus monkeys. Both lipoprotein preparations influenced the metabolic parameters measured in a similar manner in cells from both hypo- and hyperresponder animals. Exposure of skin fibroblasts to low density lipoproteins resulted in a stimulation of cholesterol esterification and a suppression of cholesterol synthesis in cells from both hypo- and hyperresponder animals. When incubated with increasing concentrations of low density lipoprotein cholesterol, up to 50 μg/ml, fibroblasts from both hypo- and hyperresponding animals responded with a similar maximum percentage suppression of sterol synthesis. Thus, hyperresponsiveness to dietary cholesterol in squirrel monkeys, although a heritable characteristic, is not associated with an inability of low density lipoprotein to suppress cholesterol synthesis or stimulate cholesterol esterification as occurs in familial hypercholesterolemia in man.

Hypothyroidism, an important cause of reversible hyperlipidemia

Primary hypothyroidism was found to be the cause of hyperlipidemia in 22 patients. The mean age was 46 years, 59% were males, 27% had vascular disease, 14% had xanthomas and 86% had thyroid antibodies. Familial involvement was shown in 3 propositi. All patients were treated with L-thyroxine, 0.05−0.2 mg/day for a mean of 16 months. Combined hyperlipidemia was common (77%), and lipoprotein phenotyping revealed types IIB hyperlipoproteinemia in 11, IIA in 5, III in 3 and IV in 3 patients. With treatment, normal plasma cholesterol (< 265 mg/dl) and triglycerides (<200 mg/dl) were obtained in 91% and 86%, respectively. The mean maintenance L-thyroxine dose was 0.15 mg/day, but smaller doses often showed marked hypolipidemic effect. The mean ± S.D. pretreatment fasting plasma cholesterol and triglycerides were 387 ± 120 and 328 ± 247 mg/dl and on thyroid treatment the mean minimum levels were 205 ± 46 and 133 ± 65 mg/dl, respectively (both p values <0.005). Hypothyroidism has proved to be a common reversible form of hyperlipidemia. One cardiac patient died and three others had to have their L-thyroxine titrated to prevent angina. Family screening has been of use in case finding for auto-immune disease in 3 families.

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.

EFFECT OF GLUCAGON ON BLOOD-CHOLESTEROL LEVELS IN RATS

The chronic administration of glucagon was found to reduce the normal plasma-cholesterol of stock-fed rats and to prevent completely the occurrence of hypercholesterolæmia regardless of their exposure to hypercholesterolæmia-inducing processes. The results suggest that this hormone may be the most potent endogenous agent of the body in the regulation of plasma-cholesterol.

Plasma lecithin-cholesterol acyltransferase and erythrocyte lipids in liver disease.

Abstract. Plasma lecithin‐cholesterol acyltransferase (LCAT) activity was reduced to approximately one fourth of normal values in patients with chronic parenchymatous liver disease without marked jaundice (mean serum bilirubin 2.0 mg/dl). A significant increase in red cell cholesterol was concomitantly demonstrated with a highly significant correlation between red cell cholesterol content and the concentration of plasma‐free cholesterol.In patients with marked obstructive jaundice (mean serum bilirubin 14.6 mg/dl) the plasma LCAT activity was even lower and in some hardly detectable. This reduced activity could not be explained by LCAT inhibition in plasma. Erythrocyte cholesterol content was markedly increased up to twice the normal values. A significant increase in erythrocyte lecithin and significant decreases in sphingomyelin and phosphatidyl ethanolamine were also found. Erythrocyte cholesterol content was found to be normal in patients with hyperbetalipoproteinemia and marked elevation of plasma total cholesterol with normal plasma cholesterol esterification.

Plasma Cholesterol Concentration

Today, a plasma cholesterol determination is considered necessary in any general examination of an adult. The exact clinical significance, however, of even a normal plasma cholesterol level is almost as much a mystery today as it was four decades ago. Indeed we still do not know of any absolutely necessary function that cholesterol in plasma performs. Even its demonstrated conversion into bile acid or into steroidal hormones does not appear to be an exclusive, or even necessary, mode for the production of these substances. Like urate, plasma cholesterol also may represent a biologically superfluous waste product, discharged by myriads of intracellular steroid reactions throughout the body. We also have no proof that an abnormal plasma cholesterol level necessarily results from some disorder in either the anabolic or catabolic phases of cholesterol metabolism itself. Actually, the aqueous solubility of cholesterol itself is so minute in the absence of its triglyceride-phosphatide-protein congeners

HYPERCHOLESTEROLEMIC EFFECT OF MENHADEN OIL IN THE PRESENCE OF DIETARY CHOLESTEROL IN SWINE.

SummaryThirty male miniature swine were fed a beef tallow basal ration supplemented with crude soybean phosphatides and menhaden oil with and without 0.5% cholesterol for a period of 48 weeks. The animals that received no cholesterol supplement all maintained normal plasma cholesterol values (75–85 mg %). The swine fed soybean phosphatides plus cholesterol showed no change in plasma cholesterol values. The swine fed beef tallow showed on cholesterol supplementation a rise in plasma cholesterol, but returned to normal in 12 weeks. The swine fed menhaden oil showed a 100% increase in plasma cholesterol when supplemented with 0.5% cholesterol and, although this level decreased, it remained substantially above the remaining groups throughout the experiment. Fecal analyses of cholesterol showed much less cholesterol in the feces of fish oil-fed pigs supplemented with cholesterol, indicating that the fish oil (or the highly unsaturated fatty acids in fish oil) may have facilitated the absorption of the dietary ...

Plasma and Red Cell Cholesterol

Abstract The experimental production of hypercholesteremia in rabbits by three independent methods—namely, high-fat feeding, cortisone injection, and Tween-80 injection—results in an elevated plasma total cholesterol, whereas the total RBC cholesterol remains constant. Previous work on plasma and red cell cholesterol in humans has been substantiated. Normal total plasma and red cell cholesterol values are 187 ± 32 and 129 ± 20 mg.%, respectively. Elevated plasma total cholesterol occurring in coronary arteriosclerosis, diabetes, nephritis, hypothyroid, Hodgkin's disease, and obesity does not affect the erythrocyte levels. Elevated erythrocyte total cholesterol levels occur in sickle cell and pernicious anemia accompanied by slightly sub-normal plasma levels. A hypothesis is advanced to explain the variability of plasma cholesterol and the relative constancy of red cell cholesterol.