Biomedical subjects
Publications and source records attributed to G E Mott.
Cholesterol has been immobilized on Sepharose-6B via oxyether linkages to the 3- or 25-position. The 3- or 25-hydroxysterol methanesulfonates were coupled with epoxy-Sepharose-6B at 80 degrees C for 24 h. Approximately 2% of the ligand was incorporated into the gel. These types of affinity columns may be useful in purifying proteins that specifically bind or metabolize cholesterol.
We measured the effects of dietary cholesterol (0.24 vs 0.0024 mg/kJ), type of dietary fat [saturated, a ratio of polyunsaturated to saturated fatty acids (P:S) of 0.37, vs unsaturated (P:S of 2.2)], and sex on biliary lipid and bile acid conjugate composition of 80 adult pedigreed baboons. From these data we calculated the bile cholesterol saturation index and the bile acid hydrophobicity index. Dietary cholesterol significantly increased the bile cholesterol concentration by 25% and the bile cholesterol saturation index by 15%, but did not significantly affect the bile acid conjugate composition or the bile acid hydrophobicity index. Diets high in saturated fatty acid compared with unsaturated fatty acid significantly decreased the bile cholesterol concentrations by 26% and the saturation index by 23%. Saturated fatty acid also decreased the proportion of hydrophobic bile acids and lowered the bile hydrophobicity index. Male baboons had a higher cholesterol saturation index and a lower hydrophobicity index than females. Dietary cholesterol and saturated fatty acid independently influence the bile lipid composition and the cholesterol saturation index.
This study was designed to determine the differences in cholesterol metabolism due to dietary cholesterol and type of fat in adult baboons. From weaning at 16 wk to 7-8 y of age, 80 baboons were fed one of four diets: high cholesterol (0.24 mg/kJ) or low cholesterol (0.0024 mg/kJ) with 40% of energy from saturated fat [polyunsaturated/saturated fatty acid ratio (P/S) = 0.37] or unsaturated fat (P/S = 2.1). High cholesterol and saturated fat independently raised serum lipoprotein and apolipoprotein concentrations to about the same extent. The liver cholesterol concentration of baboons fed high cholesterol diets was 23% higher than that of baboons fed low cholesterol. High dietary cholesterol also increased bile cholesterol concentration by 25%, the neutral steroid excretion rate by 66% and the bile acid excretion rate by 30%. With feeding of saturated fat, compared with unsaturated fat, liver cholesterol was 24% lower, bile cholesterol 26% lower and the neutral steroid excretion rate 12% lower. Dietary cholesterol greatly suppressed whole-body cholesterol synthesis, but type of fat did not affect cholesterol synthesis rate. These results suggest that dietary cholesterol and saturated fat increase plasma lipoprotein concentrations through different physiological mechanisms.
A polymorphic Pvu II site was mapped to intron 5 of LCAT, the gene encoding baboon lecithin: cholesterol acyltransferase (LCAT). In a study of 83 baboons, heterozygous baboons (Pv1/Pv2) had significantly higher LCAT enzyme activity levels than did baboons homozygous for the more common allele (Pv1/Pv1). LCAT genotype explained 6% of the total variation in LCAT enzyme activity. To test for allelic effects on cholesterol metabolism, we compared serum concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I). We also compared distributions of cholesterol and apo A-I among three HDL size classes (HDL1, HDL2, and HDL3). All measurements were obtained for each baboon after long-term feeding of a basal diet low in cholesterol and fat and again after 7 weeks on an atherogenic diet. Heterozygous baboons had significantly lower serum levels of total cholesterol than did homozygotes. In addition, we detected significant effects of LCAT genotype on size distributions of HDL cholesterol and apo A-I on both diets but did not detect any genotype-by-diet interaction. Heterozygotes had increased amounts of cholesterol and apo A-I in HDL3 particles and lower amounts of cholesterol and apo A-I in the larger HDL size classes by comparison with homozygotes. Overall, the LCAT polymorphism explained a significant proportion of total variation in cholesterol (4-10%) and apo A-I (13%) distributions on both diets. Thus, the results indicate that the LCAT polymorphism is associated with significant differences in LCAT enzyme activity and with alterations in HDL compositions.
We previously reported that female baboons overfed during infancy were not fatter at weaning, but developed hypertrophic obesity after puberty. To clarify the mechanisms of this dietary effect on adipocyte hypertrophy, we determined the effects of infant overfeeding on preweaning plasma hormone and triglyceride levels and their relationship with fat cell volume at weaning (19 weeks of age). Newborn female baboons from 3 sires and 24 dams were fed either 280 kilojoules (normally fed; n = 12) or 395 kilojoules (overfed; n = 10) per 100 g Similac formula for 18 weeks. Both formulas contained 9.2%, 43.1%, and 48.5% of calories as protein, carbohydrate, and fat, respectively. During the first 9 weeks, overfed infants had significantly higher fasting and postprandial insulin, total T3, and free T3 concentrations; lower cortisol levels; and lower excretion of urinary 17-hydroxycorticosteroids (17-OHCS) than normally fed infants. These effects were no longer significant at 17-18 weeks. Infant diet did not influence fasting and postprandial plasma triglyceride levels, and fat cell volume was not influenced by energy intake. However, fat cell volume was positively associated with postprandial triglyceride concentrations and inversely associated with postmeal nadir cortisol levels. These results demonstrate that infant overfeeding initiates early alterations in insulin, T3, free T3, and cortisol, but these effects persist only as long as there is a significant increase in energy intake.
Selective breeding of baboons has produced families with increased plasma levels of large high density lipoproteins (HDL1) and very low (VLDL) and low (LDL) density lipoproteins when the animals consume a diet enriched in cholesterol and saturated fat. High HDL1 baboons have a slower cholesteryl ester transfer, which may account for the accumulation of HDL1, but not of VLDL and LDL. To investigate the mechanism of accumulation of VLDL + LDL in plasma of the high HDL1 phenotype, we selected eight half-sib pairs of baboons, one member of each pair with high HDL1, the other member with little or no HDL1 on the same high cholesterol, saturated fat diet. Baboons were fed a chow diet and four experimental diets consisting of high and low cholesterol with corn oil, and high and low cholesterol with lard, each for 6 weeks, in a crossover design. Plasma lipids and lipoproteins and hepatic mRNA levels were measured on each diet. HDL1 phenotype, type of dietary fat, and dietary cholesterol affected plasma cholesterol and apolipoprotein (apo) B concentrations, whereas dietary fat alone affected plasma triglyceride and apoA-I concentrations. HDL1 phenotype and dietary cholesterol alone did not influence hepatic mRNA levels, whereas dietary lard, compared to corn oil, significantly increased hepatic apoE mRNA levels and decreased hepatic LDL receptor and HMG-CoA synthase mRNA levels. Hepatic apoA-I message was associated with cholesterol concentration in HDL fractions as well as with apoA-I concentrations in the plasma or HDL. However, hepatic apoB message level was not associated with plasma or LDL apoB levels. Total plasma cholesterol, including HDL, was negatively associated with hepatic LDL receptor and HMG-CoA synthase mRNA levels. However, compared with low HDL1 baboons, high HDL1 baboons had higher concentrations of LDL and HDL cholesterol at the same hepatic mRNA levels. These studies suggest that neither overproduction of apoB from the liver nor decreased hepatic LDL receptor levels cause the accumulation of VLDL and LDL in the plasma of high HDL1 baboons. These studies also show that, in spite of high levels of VLDL + LDL and HDL1, the high HDL1 baboons had higher levels of mRNA for LDL receptor and HMG-CoA synthase. This paradoxical relationship needs further study to understand the pathophysiology of VLDL and LDL accumulation in the plasma of animals with the high HDL1 phenotype.
A plasmalogen, plasmenylethanolamine, is required for in vitro growth of strains of Eubacterium which convert cholesterol to coprostanol. Plasmenylethanolamine was isolated from calf brain by selective saponification of lipid fractions separated by thin-layer or column chromatography. Cholesterol-containing thioglycolate broth plus purified plasmenylethanolamine or its 2-lyso derivative supported growth of Eubacterium ATCC 21408 and a cholesterol-reducing Eubacterium isolated from baboon feces. Plasmenylethanolamine obtained from commercial sources also supported growth of these organisms, but none of a number of other pure lipids would support growth. Metabolism of the alkenyl ether group of plasmenylethanolamine occurred during growth.
The predominant bacterial genera of baboon feces were enumerated and identified by established procedures. The predominant genera isolated were Lactobacillus, Eubacterium, Streptococcus, and Bacteroides.
One hundred three baboon infants, the progeny of an equal number of dams and seven sires, were breast fed or were fed prepared formulas containing 1.2, 29, or 61 mg/dl cholesterol for 14 weeks. We measured serum cholesterol and triglyceride concentrations at birth and at 3-week intervals, and cholesterol absorption at 12 weeks. Dietary cholesterol had a significant effect on serum cholesterol concentration at 12 weeks and on cholesterol absorption, but did not affect weight or serum triglyceride concentration. Sire had a significant effect on serum cholesterol concentration at birth and at 12 weeks, but the effect at birth did not predict the effect at 12 weeks. Sire did not affect cholesterol absorption, serum triglyceride concentration, or weight at 12 weeks. The sire effect on serum cholesterol concentration in infancy is not mediated by control of cholesterol absorption. Males weighed more than females at 12 weeks, but sex did not affect serum cholesterol concentration, triglyceride concentration, or cholesterol absorption.
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One hundred twenty-six adult female baboons (Papio cynocephalus) were hysterectomized and all except 18 were ovariectomized. The animals were fed a moderately atherogenic diet (40% calories form hydrogenated vegetable oil, 1.5 gm cholesterol/kcal) for two years. Ovariectomized-hysterectomized animals received estrone sulfate, ethynyl estradiol, or diethylstilbestrol orally in daily doses similar to those given humans. An ovariectomized-hysterectomized group and a hysterectomized group received no drug. The average total serum cholesterol concentration rose from 136 mg/dl to 223 mg/dl and declined to 186 mg/dl. Concentrations of cholesterol, triglyceride, and phospholipid in whole serum, low density lipoproteins and high density lipoproteins showed no consistent statistically significant differences among the groups. Triglyceride and phospholipid concentrations were higher in the estrogen-treated and intact-ovary groups than in the ovariectomized nonestrogen treated group, but not all pairwise comparisons were statistically significant. There were no consistent statistically significant differences in atherosclerotic lesions among the groups. Neither ovariectomy nor estrogen replacement influence diet-induced experimental atherosclerosis in the baboon within two years.
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