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We tested the hypothesis that breast and formula feeding differentially affect hepatic mRNA concentrations for LDL receptor (LDL-R) and apolipoproteins A-I, B and E in infant baboons during the preweaning period. The mRNA concentrations were measured in liver biopsies obtained prior to weaning at 14 weeks from 43 baboons that were either breast-fed (n = 17) or fed formulas with a high (n = 12) or low (n = 14) polyunsaturated/saturated (P:S) fat ratio. Breast-fed baboons had 99% higher LDL-R mRNA concentrations compared with infants fed formulas, but there were no differences among breast and formula-fed baboons in mRNA concentrations of apolipoproteins A-I, B or E. The fatty acid P:S ratio of the formulas did not affect hepatic LDL-R or apolipoprotein mRNA concentrations. These results suggest that breast-feeding increases LDL-R gene expression even though breast milk is higher in cholesterol and saturated fat compared with formulas.

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.

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.

We tested the hypothesis that infant cholesterol intake and breast- versus formula-feeding influence the bile cholesterol saturation index and bile acid conjugate composition in adult baboons at 7-8 years of age. We also measured the influence of the postweaning intake of dietary cholesterol and fat (saturated and unsaturated) on the effects of the infant diets. The 80 baboons were derived from six sires and 80 dams and randomly assigned at birth to breast-feeding or to one of three formulas containing about 2, 30, or 60 mg cholesterol/dl. After weaning at 16 weeks of age the animals were assigned to one of four adult diets, which contained 0.01 or 1.0 mg/kcal of cholesterol containing 40% of calories from saturated or unsaturated fat. The bile cholesterol saturation index was significantly higher at 7-8 years of age in baboons breast-fed as infants compared with those fed formula (87.0% versus 72.8%, p less than 0.004). The cholesterol saturation index was not significantly different among the three formula groups. Among baboons who were breast-fed and subsequently fed saturated fat as adults, the glycine/taurine (G/T) ratios of the bile acid conjugates were about three times those of baboons fed unsaturated fat (1.53 versus 0.47); whereas among formula-fed animals the type of fat did not influence the G/T ratio (interaction, p = 0.022). Adult baboons fed the three formulas in infancy had an inverse relationship of the G/T ratio to the level of formula cholesterol (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of 2 different dietary fats (40% of calories from corn oil or coconut oil), in the presence of high-dietary cholesterol (1.7 mg/kcal), on the lipoprotein profiles of baboons (Papio cynocephalus sp) were studied by analytic ultracentrifugation, gradient gel electrophoresis (GGE), and heparin-manganese chloride precipitation. Relative to the corn oil (polyunsaturated fat) diet, the coconut oil (saturated fat) diet significantly increased total serum cholesterol by 43% (P less than 0.001) by increasing non-precipitable cholesterol (HDL-C) 58% (P less than 0.001) and precipitable cholesterol (VLDL + LDL-C) 35% (P less than 0.001). Analytic ultracentrifugal observations indicated that the increase in HDL-C was due to considerable increases in both HDL-I (baboon HDL of size 100-125 A and hydrated density 1.063-1.120 g/ml) and F1.20 degrees 9-28 lipoproteins (material of size 125-220 A and hydrated density 1.03-1.08 g/ml, and containing HDL apolipoproteins and apo E). Concentrations of other HDL subpopulations were unaffected by the dietary saturated rat. The increase in VLDL + LDL-C was due to increased LDL (S degree F 5-12 lipoproteins) and, to some extent, F1.20 degrees 9-28 lipoproteins because the larger, faster floating subspecies of the F1.20 degrees 9-28 lipoproteins were precipitable by heparin-manganese. In contrast, saturated fat (relative to polyunsaturated fat) induced lower concentrations of IDL (SF degree 12-20) and VLDL (SF degree 20-100). Lipoprotein size distributions by GGE indicated 5 HDL subpopulations and 2 or more LDL subpopulations in the sera of most baboons. The type of dietary fat did not affect the particle size range of each of the the HDL or LDL subpopulations. The results indicate that dietary fat markedly modulates the distribution of cholesterol between apo A-I-containing (HDL and F1.20 degrees 9-28) and apo B-containing (IDL and VLDL) lipoproteins without altering the presence of subpopulations based on particle size.

In separate experiments, we fed 30 male and 25 female baboons a diet enriched in cholesterol and saturated fat for periods of 3.3 and 2.6 years. Using operant conditioning with water rewards, we trained the animals to puff on smoking machines in a human-like manner. Half of the animals smoked more than 40 cigarettes per day, while the remaining animals (controls) puffed air. Initially, the diet produced twofold (males) and threefold (females) elevations from baseline levels in serum cholesterol concentrations, but over the course of the experiments, the serum cholesterol decreased to 1.5 (males) and 2.0 (females) times baseline levels in both cigarette smokers and controls. Blood carbon monoxide concentration, plasma thiocyanate concentration, and urine cotinine concentration were significantly greater in smokers than in controls. Responses to smoking in males included lymphocytosis, elevated fasting blood glucose concentration, and decreased seminal vesicle weight. In females, hemoglobin and mean corpuscular hemoglobin concentrations were elevated. The extent of atherosclerosis was examined after 2.8 (males) and 1.6 (females) years of smoking. Among males, the extent of lesions in carotid arteries was significantly greater in smokers than in controls, but there were no significant differences in atherosclerosis in the aorta or the brachial, iliac-femoral, or coronary arteries. Among females, there were no significant differences in atherosclerosis between smokers and controls in any artery. These experiments show little effect of 2 to 3 years of cigarette smoke inhalation and concurrent modest elevation of blood carboxyhemoglobin on experimental atherosclerosis in the presence of moderate hyperlipidemia.

Some progeny of baboons (Papio sp.) selectively bred for a high response of serum cholesterol to an atherogenic diet have high serum levels of unusual lipoproteins with flotation rates of F degrees 1.20 9-28, intermediate between those of low and high density lipoproteins (HDL). They are similar to the fraction of HDL commonly called HDL1. We conducted a cross-over experiment to determine the roles of dietary cholesterol and saturated fat in eliciting these lipoproteins in the progeny of two affected sires. Half of the progeny of each sire manifested the trait (high HDL1 phenotype) while consuming an atherogenic diet and half did not (low HDL1 phenotype). While consuming a chow diet, high HDL1 progeny had higher total serum cholesterol concentrations than did low HDL1 progeny. This difference was exaggerated when the animals consumed diets enriched in either cholesterol or saturated fat (lard), and was greatest when the diet contained both. High HDL1 animals also had considerably higher serum apo E concentrations, and slightly higher serum apo A-I concentrations. High HDL1 progeny had much higher levels of cholesterol (twofold) and of apo A-I (three- to eightfold) in HDL1 fractions than did low HDL1 progeny. There were significant interactions between HDL1 class and both dietary cholesterol and saturated fat in their effects on other lipoprotein fractions. High HDL1 animals had an exaggerated elevation of cholesterol and apo B in very low, intermediate, and low density lipoproteins in response to dietary cholesterol. They also had an exaggerated elevation of cholesterol in the lighter HDL1 fraction (d = 1.041-1.053), and lesser elevation of cholesterol and apo A-I in HDL2.

Positive assortative mating of baboons (Papio sp.) based on elevation of serum cholesterol concentrations in response to a cholesterol- and saturated fat-enriched diet produced 64 progeny (30 high line; 34 low line). When the animals were 3 to 4 years of age, we tested their lipoprotein cholesterol responses to dietary cholesterol and fat in a factorial experiment with two levels of dietary cholesterol (1.7 and less than 0.01 mg/kcal) and two types of fat, coconut oil (P/S 0.1) and corn oil (P/S 3.5), each providing 40% of total calories from fat; we also tested their responses to chow. The high line animals had significantly higher very low density plus low density lipoprotein (VLDL + LDL) and high density lipoprotein (HDL) cholesterol levels on all diets. The effects of dietary cholesterol on VLDL + LDL cholesterol concentrations were greater in high line animals than in low line animals, but dietary cholesterol's effects on HDL cholesterol were similar in both lines. The effects of saturated fat, compared to unsaturated fat, on both VLDL + LDL and HDL cholesterol levels were similar in both lines. Selective breeding produced lines diverging in lipoprotein cholesterol concentrations by acting on several different genetically mediated processes that control serum lipoprotein levels. At least one of these processes involves responsiveness of serum VLDL + LDL cholesterol concentration to dietary cholesterol.

We analyzed the effects of dietary cholesterol, type of dietary fat, sex and sire progeny family on lecithin-cholesterol acyltransferase activity in 80 adult baboons. The animals were the progeny of 80 dams and 6 sires and were randomly assigned at birth to breast feeding or to one of three formulas containing 0.02, 0.30 or 0.60 mg cholesterol/ml. After weaning at 4 months of age the animals were fed one of four diets that were either high or low in cholesterol with 40% of the calories from either saturated or unsaturated fat. The fractional and molar rates of lecithin-cholesterol acyltransferase activity were measured at 7-8 years of age by an HPLC method. Infant diet (breast vs. formula feeding or level of cholesterol in formula had no effect on enzyme activity later in life. The adult diets that were high in cholesterol decreased the fractional lecithin-cholesterol acyltransferase rate by 20% / compared to diets low in cholesterol (7.89 vs. 9.84%/h, P less than 0.002), but dietary cholesterol did not affect the molar activity. Animals fed the high cholesterol diets had higher unesterified cholesterol concentrations compared to those fed the low cholesterol diets (38.1 mg/dl vs. 31.6 mg/dl, P less than 0.0001). The molar lecithin-cholesterol acyltransferase rate was increased 13% by saturated compared to unsaturated fat (83.3 vs. 73.6 nmol/h per ml plasma, P less than 0.07), but no effect of dietary fat was observed on the fractional enzyme activity. Females compared to males had significantly higher fractional (10.9 vs. 7.14%/h, P less than 0.0001) and molar lecithin-cholesterol acyltransferase activities (99.3 vs. 61.7 nmol/h per ml plasma, P less than 0.0001). After adjustment for the effects of diet and sex we observed differences in the fractional activity (range, 7.2-10.8%/h, P less than 0.04) and in the molar rate (range, 63.6-99.8 nmol/h per ml plasma, P less than 0.07) among the six sire progeny groups. The differences among sire progeny groups are evidence for genetic differences in lecithin-cholesterol acyltransferase activities among the baboon families.

The influence of restricting either the fat or the mineral component of the diet to the same extent as they are restricted in the life-prolonging, food-restriction paradigm but without restricting calories was studied in regard to longevity and age-related pathologic lesions of barrier-maintained male Fischer 344 rats. Neither the restriction of fat nor the restriction of mineral influenced the median length of life or maximum life span as indicated by the age of the 10th percentile survivors. Restricting the dietary fat did retard the development of chronic nephropathy and associated lesions, but it also increased the prevalence of lymphoma and leukemia. The development of chronic nephropathy was not significantly affected by restricting the mineral component of the diet.