Measurment of rhesus monkey (Macaca mulatta) apolipoprotein B in serum by radioimmunoassay: comparison of immunoreactivities of rhesus and human low density lipoproteins.

A sensitive and specific double antibody radio-immunoassay for the major apolipoprotein (apoB) of rhesus (Macaca mulatta) serum very low density lipoprotein (VLDL) and low density lipoprotein (LDL) is described. The anti-serum was raised to LDL (d 1.030-1.040 g/ml) and the LDL(2) (d 1.020-1.050 g/ml) was labeled with (125)I by the chloramine-T or iodine monochloride method. The assay, which was sensitive to 0.02-0.5 micro g of LDL(2), had an inter-assay coefficient of variation of 4.5%. This assay was successfully used to measure apoB in the whole serum and low density lipoproteins of control monkeys maintained on a standard Purina monkey chow (PMC) diet and of three groups of monkeys fed atherogenic diets: an "average American diet," a 25% peanut oil and 2% cholesterol-supplemented PMC diet, and a 25% coconut oil and 2% cholesterol-supplemented PMC diet. The control monkeys (n = 13) had a serum cholesterol of 146 +/- 28 mg/dl and an apoB of 50 +/- 18 mg/dl. In the monkeys maintained on the atherogenic diets the serum apoB was elevated: 103 +/- 28 mg/dl (American), 102 +/- 35 mg/dl (peanut oil), and 312 +/- 88 mg/dl (coconut oil). The values for serum total cholesterol were 333 +/- 65 mg/dl (American), 606 +/- 212 mg/dl (peanut oil), and 864 +/- 233 mg/dl (coconut oil) and were elevated relative to controls (P < 0.001). For each of the diets, total serum cholesterol correlated with serum apoB (P < 0.001). The slopes of the regression lines of serum apoB vs. cholesterol for the monkeys on the PMC, American, and coconut oil diets were similar (m = 0.531, 0.401, and 0.359, respectively), but differed from that of monkeys on the peanut oil diet (m = 0.121). The immunoreactivities of rhesus and human LDL were compared using specific antisera raised against these antigens. In homologous assay systems, monkey and human LDL exhibited unique immunological determinants. The same results were obtained with the delipidated preparations of the two LDLs using antisera raised against either monkey or human apoB. Crossover studies using a heterologous tracer with each anti-serum resulted in the selection of a specific population of antibodies directed against antigenic sites shared by these two LDL species.     

Cholelithiasis in a male rhesus monkey (Macaca mulatta) fed a cholesterol-containing diet.

In this report we describe the development of cholelithiasis in a male rhesus monkey fed a cholesterol-containing diet for 24 months. This represents the only case of cholelithiasis in this species of nonhuman primate that we have observed out of a population of over 500 rhesus monkeys fed similar cholesterol-containing diets. Associated with the appearance of gallstones was the production of bile saturated with cholesterol, and the excretion of bile with an abnormal bile acid composition.     

Studies on the regulation of plasma cholesterol levels in squirrel monkeys of two genotypes

Certain individual squirrel monkeys ("hypo-responders") are able to remain normocholesterolemic when fed diets containing cholesterol (0.5 mg/kcal). Other squirrel monkeys ("hyperresponders") when fed the same diet become hypercholesterolemic. The purpose of these studies was to identify the mechanisms which allow hyporesponders to compensate for dietary cholesterol. Using formula diets and sterol balance techniques, we have compared cholesterol absorption, synthesis, excretion, and turnover in hypo- and hyperresponding monkeys. Cholesterol absorption was essentially identical in the two groups (about 55 mg/day). Cholesterol synthesis was likewise similar in the two groups (about 35 mg/day) and there was no evidence of feedback inhibition at the level of cholesterol fed. Hyporesponders had faster turnover rates and smaller body cholesterol pools than did hyperresponders. Excretion of neutral steroids was similar for hypo- and hyperresponders and did not change with cholesterol feeding. In contrast, hyporesponders increased bile acid excretion shortly after cholesterol feeding was begun. Hyperresponders responded more slowly and to a lesser degree. It is concluded that, in this species, the mechanism of control of plasma cholesterol levels is related to the rate of conversion of cholesterol to bile acids.     

The effects of dietary fat and cholesterol on the metabolism of plasma low density lipoprotein apoproteins in squirrel monkeys.

Low density lipoprotein apoproteins from squirrel monkeys (Saimiri sciureus) had characteristic 2-phase die-away curves in plasma. The kinetic constants were similar with three methods of labeling: in vitro with 125I by the iodine monochloride or the Bolton-Hunter methods or in vivo by the injection of [3H]-leucine into a donor animal. Dietary cholesterol and the type of dietary fat influenced the concentration of plasma cholesterol and low density lipoproteins. The fractional turnover of low density lipoprotein apoprotein was greaterin monkeys fed semipurified diets with safflower oil than in those on butter but was not influenced by dietary cholesterol. The total low density lipoprotein apoprotein turnover (the product of fractional turnover and plasma lipoprotein concentration) was highest in monkeys fed butter plus added cholesterol and lowest in those on safflower oil without cholesterol. Dietary safflower oil resulted in a smaller proportion of the total low density lipoprotein pool in the intravascular compartment than did butter, regardless of whether cholesterol was added.     

Genetically determined hypercholesterolemia in a rhesus monkey family due to a deficiency of the LDL receptor

A family of rhesus monkeys comprising a sire, a dam, and four male offspring were fed a cholesterol-free Purina Chow diet for several months. The sire, 431-J, and two of the offspring, B-8204 and B-8806, had persistent plasma cholesterol levels in the range of 100-130 mg/dl, whereas the dam, 766-I, and the two other offspring, B-1000 and B-7643, exhibited a marked hypercholesterolemia in the 250-300 mg/dl range associated with an elevation of plasma LDL and apoB. When fed for 12 weeks a diet containing 12.5% lard and 0.25% cholesterol, sire, dam, B-1000 and B-7643 exhibited a marked hypercholesterolemia (500-800 mg/dl range), whereas B-8204 and B-8806 developed only a modest hypercholesterolemia (200-250 mg/dl). All animals were Lp[a]+. Skin fibroblasts from each animal and from control cells were grown in 10% fetal calf serum, transferred to 10% lipoprotein-deficient serum for 48 hr, and then incubated at 4 degrees C or 37 degrees C with 125I-labeled Lp[a]-free LDL. The fibroblasts from dam and offspring B-1000 and B-7643 bound and internalized 125I-labeled LDL less efficiently than control cells. Mathematical analyses of the 4 degrees C binding data indicated that there were no significant differences in LDL binding affinity between test and control cells suggesting that cells from the animals with a spontaneous hypercholesterolemia had a decreased number of LDL receptors. This conclusion was supported by the results of ligand and immunoblot analyses carried out on cell lysates separated by gradient gel electrophoresis. We conclude that a genetically determined LDL receptor deficiency was responsible, in part, for the spontaneous hypercholesterolemia observed in three out of the six family members and that this deficiency accounted for the hyperresponsiveness to a dietary fat and cholesterol challenge by the dam and the two offspring, B-1000 and B-7643. The hyperresponsiveness noted in the sire that had no evidence for LDL-receptor deficiency illustrates that factors other than the LDL receptor were responsible for the hypercholesterolemia attending the fat challenge.     

高反应与低反应猴在诱发动脉粥样硬化过程中血脂改变规律的观察

喂饲高脂高胆固醇饮食是诱发实验性动脉粥样硬化（简称AS）的基本方法。在诱发AS过程中,血清脂质的改变不但有种属差异,也存在个体反应性的差异。猴是用于AS研究最理想的实验动物。喂以高胆固醇饮食后,有些猴血清胆固醇上升速度明显高于一般同种猴,称高反应猴（High-responding rhesus monkey）;另一些猴的血清胆固醇上升十分缓慢,低于同种猴的一般反应速度,称低反应猴（Low-responding rhesusmonkey）。关于高反应猴（简称HI）及低反应猴（简称LO）在诱发AS过程中血清胆固醇反应的差别,国外已有报道。（Baker et al.,1981;Bhattacharyya et al.,1977;     

Establishment and ultrasound characteristics of atherosclerosis in rhesus monkey

Background

Atherosclerosis is one of the main risk factors cause acute cerebral-cardio vascular diseases. It's of great significance to establish an atherosclerosis animal model that can mimic the characteristics and nature course of human patients. Therefore, a rhesus monkey model was induced by high-fat diet to monitor their lipid profile and intima-media thickness (IMT) of artery walls and study atherosclerosis progression.

Methods

Fifty male rhesus monkeys were enrolled in this study. All of these monkeys were aged 7 to 14 years with BMI >30 kg/m². They were fed with high-fat diet containing 10% of fat for the first 48 weeks. Use ultrasound to measure the IMT at bilateral common carotid arteries and their bifurcations and aorta (AO) of the monkeys, and screen out the individuals with thickened IMT for the next phase. In the next 48 weeks, some of these monkeys (n = 4) were fed with standard diet containing 3% fat. Meanwhile the other monkeys (n = 5) were fed with high-fat diet for another 48 weeks. Their serum lipid level was monitored and arterial IMT was also determined periodically.

Results

Serum lipid level of all 50 monkeys elevated after fed with high-fat diet for the first 48 weeks. IMT thickening at right common carotid bifurcation and aorta (AO) was thickened in 9 monkeys. Furthermore, 4 of these 9 monkeys were fed with standard diet and other 5 monkeys were fed with high-fat diet in the following 48 weeks. The serum lipid level of the 4 monkeys recovered and their IMT at RBIF and AO did not progress. However, the lipid level of other 5 monkeys remained high, and their IMT thickening of AO progressed, and plaques and calcification focuses were found at the anterior wall of aorta near the bifurcation of common iliac artery.

Conclusions

After high-fat diet induction for 96 weeks, serum lipid levels of rhesus monkeys elevated significantly, which subsequently caused IMT thickening and plaques formation. When IMT thickening occurred, further vascular injury may be prevented by reducing diet fat content. Our study indicates that vascular injury of high-fat diet induced rhesus monkey is similar to that of human in position and progression.

     

Hepatic perfusate very low density lipoproteins obtained from fat-fed nonhuman primates stimulate cholesterol esterification in macrophages

The livers of both baboons and rhesus monkeys fed a high fat, high cholesterol diet secreted very low density lipoproteins (VLDL) that were enriched in cholesteryl ester and apoe as compared to VLDL secreted by the livers of chow-fed animals. Stimulation of macrophage cholesterol esterification by the experimental VLDL was compared to that produced by the standard beta-VLDL obtained from the plasma of a rhesus monkey fed 25% coconut oil plus 2% cholesterol. This standard beta-VLDL stimulated 7- to 10-fold more esterification than did the bovine albumin control. Hepatic VLDL from fat-fed animals stimulated esterification in J774 macrophages 50 to 150% as well as did the standard beta-VLDL, even though hepatic VLDL did not display beta electrophoretic mobility on agarose gel electrophoresis. Plasma VLDL from lard-fed baboons did not exhibit beta electrophoretic mobility but did stimulate esterification in macrophages. Baboons were divided into high and low responders based on the change in plasma cholesterol levels in response to a high fat, high cholesterol diet. Both plasma and hepatic VLDL from high responders stimulated cholesterol esterification, whereas hepatic VLDL obtained from low responders or chow-fed baboons did not stimulate cholesterol esterification in macrophages. There was a strong positive correlation (r = 0.866) between the number of apoE molecules per VLDL particle in VLDL obtained from chow-fed, lard-fed, or coconut oil-fed primates and the rate of cholesterol esterification in macrophages. Our results show that hepatic perfusate VLDL obtained from fat- and cholesterol-fed primates have compositional and functional properties usually ascribed to circulating beta-VLDL, without displaying beta mobility, and indicate that the liver may be an important source of atherogenic lipoproteins.     

Cortisol metabolism in the Bolivian squirrel monkey (Saimiri boliviensis boliviensis)

New World squirrel monkeys (Saimiri spp.) have high circulating cortisol levels but normal electrolytes and blood pressures. The goal of the present study was to gain insight into adaptive mechanisms used by Bolivian squirrel monkeys to minimize the effects of high cortisol on mineralocorticoid receptor (MR) activity and electrolyte and water balance. Aldosterone levels in serum from 10 squirrel monkeys were 17.7 +/- 3.4 ng/dl (normal range in humans, 4 to 31 ng/dl), suggesting that squirrel monkeys do not exhibit a compensatory increase in aldosterone. The squirrel monkey MR was cloned and expressed in COS-7 cells and found to have similar responsiveness to cortisol and aldosterone as human MR, suggesting that squirrel monkey MR is not inherently less responsive to cortisol. To determine whether altered metabolism of cortisol might contribute to MR protection in squirrel monkeys, serum and urinary cortisol and cortisone were measured, and a comprehensive urinary corticosteroid metabolite profile was performed in samples from anesthetized and awake squirrel monkeys. The levels of cortisone exceeded those of cortisol in serum and urine, suggesting increased peripheral 11beta-hydroxysteroid dehydrogenase 2 activity in squirrel monkeys. In addition, a significant fraction (approximately 20%) of total corticosteroids excreted in the urine of squirrel monkeys appeared as 6beta-hydroxycortisol, compared with that in man (1%). Therefore, changes in cortisol metabolism likely contribute to adaptive mechanisms used by Bolivian squirrel monkeys to minimize effects of high cortisol.     

Aneurysms in a large colony of squirrel monkeys (Saimiri sciureus)

This communication reports the findings of a retrospective study of extracranial aneurysms found at necropsy in a large colony of squirrel monkeys (Saimiri sciureus). Eleven (1.5%) of 730 cases had dissecting, saccular, or fusiform aneurysms of the carotid arteries or aorta. Saccular and fusiform aneurysms were found only in animals that had been fed atherogenic diets, whereas dissecting aneurysms occurred in both normo- and hypercholesterolemic monkeys. Neither the type or location of aneurysms, however, could be predicted by the length of time an animal consumed an atherogenic diet, nor by the total mean serum cholesterol concentration. The anatomical characteristics, location, and incidence of aneurysms found in squirrel monkeys resembled closely those observed in human autopsy cases.     

Effects of dietary eicosapentaenoate (20:5 n-3) on cardiac beta-adrenergic receptor activity in the marmoset monkey

Eicosapentaenoic acid (EPA; 20:5 n-3; ethyl ester) in combination with atherogenic or non-atherogenic high fat diets was fed to young adult male marmoset monkeys for a period of 30 weeks. EPA markedly reduced the raised plasma cholesterol level evident when feeding an atherogenic diet but did not influence the cardiac membrane cholesterol-to-phospholipid ratio. EPA and its elongation product 22:5 n-3 was incorporated into cardiac membrane phospholipids at the expense of linoleic and arachidonic acids. Dietary EPA increased cardiac beta-AR affinity and reversed the decreased beta-AR affinity evident when feeding an atherogenic diet.     

The influence of dietary lipid supplementation on cardiac beta-adrenergic receptor adenylate cyclase activity in the marmoset monkey

Dietary lipid supplements high in either saturated fat derived from sheep kidney fat or unsaturated fat derived from sunflower seed oil, and a low mixed fat reference diet were fed to marmoset monkeys for 20 months and the effects on cardiac membrane lipid composition, and myocardial catecholamine-stimulated adenylate cyclase and beta-adrenergic receptor binding activity were investigated. For cardiac membranes enriched for beta-adrenergic binding activity, the dietary lipid treatment resulted in small changes in the proportion of saturated to unsaturated fatty acids and substantial changes in the (n - 6) to (n - 3) series of unsaturated fatty acids in the membrane phospholipids. The sheep kidney fat diet increased the cholesterol-to-phospholipid ratio in cardiac membranes in comparison to the other diets. This diet also significantly elevated basal and isoproterenol-, epinephrine- and norepinephrine-stimulated adenylate cyclase activity. The value of the dissociation constant (Kd) and the receptor number (Bmax) for the binding of [125I]ICYP to the beta-adrenergic receptor was significantly reduced in marmosets fed the sheep kidney fat diet. These results suggest that dietary lipids can influence the activity of the beta-adrenergic/adenylate cyclase system of the heart. Modulation of this transmembrane signalling system may be induced by changes in the properties of the associated membrane lipids, particularly by alteration in the membrane cholesterol-to-phospholipid ratio. This effect may be limited to those animal species in which the nature of the dietary fatty acid intake may be influencing cardiac membrane cholesterol homeostasis, which is in agreement with previous results in rats following dietary cholesterol supplementation (McMurchie et al. (1987) Biochim. Biophys. Acta 898, 137-153). ICYP, (-)-iodocyanopindolol.     

CD45: a leukocyte-specific member of the protein tyrosine phosphatase family.

In a recent study from this laboratory, rhesus monkeys fed a 90% palm oil/10% soybean oil-containing diet (PS), rich in 16:0 and 18:1 fatty acids, had decreased total and LDL cholesterol concentrations compared to monkeys fed a 90% coconut oil/10% soybean oil-containing diet (CS), rich in 12:0 and 14:0 fatty acids. To investigate the metabolic basis of these changes, homologous 125I-VLDL and 131I-LDL were injected simultaneously into eight monkeys (four per dietary group). Analysis of apo B specific activity curves revealed that PS monkeys had an increased pool size of VLDL apo B (P less than 0.02), a 3-fold increase in the total VLDL apo B transport rate (P less than 0.001), a decreased pool size of LDL apo B (P less than 0.01) and a 2-fold decrease in the total transport rate of LDL apo B (P less than 0.001), while the irreversible FCR for VLDL apo B and LDL apo B was similar between dietary groups. PS monkeys derived a greater percentage of LDL apo B from VLDL catabolism resulting in a greater transport rate of LDL apo B from VLDL catabolism (P less than 0.055), in comparison to CS monkeys. For CS monkeys the proportion as well as the amount of LDL apo B derived from VLDL-independent catabolism (i.e., LDL apo B derived from sources other than VLDL catabolism) was higher (P less than 0.001) than the values obtained in PS monkeys. In both dietary groups the proportion of VLDL apo B converted to LDL apo B was similar, although the absolute amount was higher for the PS monkeys (P less than 0.06). The proportion of VLDL apo B directly removed from the circulation was similar for both dietary groups, with the absolute amount being higher for the PS monkeys (P less than 0.001). Consistent with the lower pool size of LDL apo B and the higher pool size of VLDL apo B observed in PS monkeys, plasma and LDL cholesterol concentrations tended to be lower, whereas plasma triacylglycerol and VLDL cholesterol concentrations tended to be higher, but these changes were not statistically significant. Although total apo B and VLDL apo B transport rates were increased 2-3-fold in PS monkeys, LDL apo B concentration was reduced by 40% (P less than 0.02) attributed to a significant reduction in the mass and proportion of LDL apo B derived independent of VLDL catabolism.(ABSTRACT TRUNCATED AT 400 WORDS)     

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 threehyporesponder squirrel monkeys, previously characterized on the basis of their plasma cholesterol response to two cholesterol-containing diets and the pheno-type 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 resultd 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 microgram/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.     

Vitamin C deficiency in captive nonhuman primates fed commercial primate diet

Scurvy was diagnosed in 19 rhesus monkeys (Macaca mulatta) and four squirrel monkeys (Saimiri sciureus) from a colony of nonhuman primates maintained on a commercial diet. Signs of weakness, reluctance to move, gingival hemorrhage, bruising, proximal and distal metaphyseal fractures, weight loss and anemia appeared in juvenile and young adult rhesus monkeys over a 2 week period. Clinical signs subsided after 5 days of vitamin C therapy. At the same time, cephalohematomas and weakness developed in squirrel monkeys, which failed to respond to treatment. These cases were associated with manufacturer's admitted error in preparation of the commercially prepared monkey diet.     

Effects of maternal marginal zinc deficiency on myelin protein profiles in the suckling rat and infant rhesus monkey

In the current study, the effects of marginal Zn deficiency on myelin protein profiles in neonatal rats and rhesus monkeys were investigated. Following mating, rats were fed a Zn-adequate diet,ad libitum (50 μg Zn/g; 50 Zn AL), or a marginal Zn diet (10 μg Zn/g) from day 0 (10 Zn d0) or day 14 (10 Zn d14) of gestation to day 20 postnatal. An additional group of dams was restricted-fed the control diet to the food intake of the 10 Zn d0 group (50 Zn RF). Day 20 pup plasma and liver Zn concentrations in the 10 Zn groups were lower than in the 50 Zn groups. In a parallel experiment, rhesus monkeys were fed a Zn-adequatead libitum diet (100 μg Zn/g) or a marginal Zn diet (4 μg Zn/g diet; MZD) throughout gestation and lactation. Day 30 monkey infant plasma and liver Zn levels were similar in the MZD and control groups. Rat brain and monkey brain cortex weights were similar among the dietary groups. The amount of myelin recovered (mg protein/g brain) from day 20 rat pups from the 10 Zn groups was lower than that recovered from the 50 Zn rat pups. Myelin recovery from the MZD and control monkey infants was similar. When myelin protein profiles were characterized, it was found that the percentages of high-molecular-weight (HMW) proteins and Wolfgram protein were higher, whereas the percentages of small and large basic proteins were lower in myelin from the 10 Zn d0 and 50 Zn RF pups compared to the distribution in the 50 Zn AL rat pups. Results for the 10 Zn d0 and 10 Zn d14 pups were similar for all of the parameters studied. The percentage of HMW proteins was higher and that of basic protein lower in myelin from MZD monkey infants compared to the percentage of these proteins in myelin from controls. Although the interpretation of the rat data is complicated because of the anorexia associated with the Zn deficiency, the observed changes in monkey myelin protein profiles provide strong evidence that maternal Zn deficiency affects myelination in the offspring.     

Differential effects of dietary fat on the tissue-specific expression of the apolipoprotein A-I gene: relationship to plasma concentration of high density lipoproteins

Isocaloric substitution of polyunsaturated fat for saturated fat reduces concentrations of total plasma cholesterol and high density lipoproteins (HDL) in nonhuman primates. The biochemical mechanisms through which polyunsaturated fat lowers plasma HDL concentrations are not well understood but must involve changes in HDL production or HDL clearance from plasma, or both. To determine whether dietary polyunsaturated fat (P/S = 2.2) alters apolipoprotein (apo) A-I production, African green monkeys (Cercopithecus aethiops) were fed diets containing polyunsaturated fat or saturated fat (P/S = 0.3) each in combination with high (0.8 mg/kcal) and low (0.03 mg/kcal) amounts of dietary cholesterol. Animals fed polyunsaturated fat at either cholesterol level had lower plasma concentrations of total cholesterol and HDL cholesterol. Plasma apoA-I concentration was reduced by 16% by polyunsaturated fat in the high cholesterol group. The rate of hepatic apoA-I secretion, as estimated by the accumulation of perfusate apoA-I during recirculating liver perfusion, was reduced by 19% in animals consuming the high cholesterol, polyunsaturated fat diet. Hepatic apoA-I mRNA concentrations, as measured by DNA-excess solution hybridization, also were reduced by 22% in the high cholesterol, polyunsaturated fat-fed animals. In contrast, intestinal apoA-I mRNA concentrations were not altered by the type of dietary fat. Plasma apoA-II and hepatic apoA-II mRNA concentrations also were not altered by the type of dietary fat. These data indicate that dietary polyunsaturated fat can selectively alter the expression of the apoA-I gene in a tissue-specific manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dietary cholesterol influences cardiac beta-adrenergic receptor adenylate cyclase activity in the marmoset monkey by changes in membrane cholesterol status

The activity of the beta-adrenergic receptor/adenylate cyclase system of the marmoset monkey heart was investigated following dietary cholesterol supplementation (0.5%). After 22 weeks, plasma cholesterol levels in the cholesterol group were more than twice that of the control group. In the cholesterol-fed group, the affinity for ICYP binding to cardiac membranes was elevated more than 2-fold, while the receptor number was decreased by 31%. Isoproterenol, norepinephrine and sodium fluoride stimulated adenylate cyclase activity was significantly higher in the cholesterol-fed group although the fold stimulation over basal levels was not affected. The most prominent change in the cardiac membrane lipids was an increase in the cholesterol to phospholipid ratio in marmoset monkeys fed cholesterol. These results indicate that in the marmoset, membrane cholesterol is an important factor in determining various properties of the cardiac beta-adrenergic receptor particularly receptor affinity which may impact on the response of the beta-adrenergic receptor/adenylate cyclase system of the heart to catecholamines. This result is in agreement with dietary fatty acid supplements designed to increase cardiac membrane cholesterol in this animal species (McMurchie, E.J. et al. (1988) Biochim. Biophys. Acta 937, 347-358). Elevated membrane cholesterol enhances beta-adrenergic receptor affinity and certain aspects of adenylate cyclase activity. This is a likely mechanism whereby atherogenic diets could promote cardiac arrhythmia in non-human primates and indeed in man.     

Effects of dietary cholesterol on adipose tissue lipoprotein lipase in the baboon

The effects of infant diet (breast milk or formula containing 2, 30 or 60 mg/dl cholesterol) and subsequent dietary cholesterol (0.02, 1.0 or 1.7 mg/kcal) and fat (saturated or unsaturated) on heparin-releasable lipolytic activity from omental adipose tissue was estimated from 99 baboons of 5-8 years of age. This lipase activity was characterized as lipoprotein lipase based on salt inhibition and apolipoprotein C-II activation. Lipoprotein lipase activity released from adipose tissue by heparin was significantly (P less than 0.002) lower in high cholesterol-fed baboons than in those fed low cholesterol. Most of this difference was due to impaired long-term heparin release of lipoprotein lipase. Adipose tissue lipoprotein lipase increased with increasing fat cell size regardless of diet, but there was no effect of diet on adipocyte size. There were no significant effects of infant cholesterol intake nor adult saturated or unsaturated fat on lipoprotein lipase activity. Adult baboons breast fed as infants had lower adipose tissue lipoprotein lipase activity (P less than 0.07) than adults fed formula as infants.     

Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin: cholesterol acyltransferase in cynomolgus monkeys

The effects of intravenous injection of lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF) were investigated in cynomolgus monkeys (Macaca fascicularis). Injection of 20 micrograms/kg of LPS from E. coli (serotype 055:B5) into cynomolgus monkeys fed a monkey chow diet caused a twofold increase in plasma triglyceride and a 25% reduction in plasma cholesterol 48 h after injection. Similar results were found with injection of recombinant human TNF at a dose of 20 micrograms/kg into chow-fed animals. However, injection of the same dose of LPS or TNF into animals fed an atherogenic diet containing saturated fat and cholesterol resulted in a 2.4- to 5-fold increase in plasma triglyceride concentrations and no significant change in plasma cholesterol levels. The fall in plasma cholesterol levels observed in chow-fed animals was associated with a 57% decrease in the cholesteryl ester (CE) content in low density lipoprotein (LDL) and 35% decrease in CE in high density lipoprotein (HDL) in LPS-injected animals, and a decrease of 33% in CE concentration of LDL and 41% in CE of HDL in animals injected with TNF. In animals fed the atherogenic diet containing saturated fat and cholesterol, the injection of both LPS and TNF also resulted in a significant decrease in the CE content of LDL and HDL. However, the plasma total cholesterol levels did not change in the animals fed saturated fat and cholesterol because the decrease in CE content of LDL and HDL was offset by an increase in very low density lipoprotein (VLDL)-CE.(ABSTRACT TRUNCATED AT 250 WORDS)