In general, protein of animal origin is more cholesterolemic and atherogenic than plant protein. The addition of single amino acids to the protein can influence cholesterolemia and atherogenicity, by either increasing or decreasing these conditions. The lysine to arginine ratio, which is higher in animal than in plant proteins, may be a factor in cholesterolemia. The results may be explained in part by the findings that lipid absorption is elevated in rabbits or rats fed animal proteins as is turnover time. Animals fed soy protein excrete more neutral and acidic steroids, and have increased activity of hepatic HMG CoA reductase and cholesterol 7α-hydroxylase. Animal protein may exert its hypercholesterolemic effect by mechanisms which include increased absorption of cholesterol and decreased turnover.

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Diets containing soybean protein generally induce low levels of serum cholesterol in experimental animals, when compared with diets containing casein. The hypocholesterolemia in animals fed soybean protein is associated with increased rates of fecal excretion of bile acids and neutral steroids, low liver cholesterol concentrations, increased numbers of hepatic apo B/E receptors, increased rates of hepatic cholesterol synthesis, increased rates of bile acid synthesis and decreased rates of lipoprotein cholesterol output by the liver. In this communication the development of the hypocholesterolemia induced by soybean protein is described. The various mechanisms that have been proposed to explain the hypocholesterolemic effect of soybean protein are scrutinized, compared and contrasted.

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Changes in the concentration and composition of serum VLDL, LDL, and HDL were studied in rabbits transferred from Chow diets to cholesterol-free, semipurified diets containing casein or isolated soy protein. During the first week on the casein diet, there was a marked increase in LDL-cholesterol and these higher levels were maintained during the subsequent 3 weeks of the study. Similar but less marked changes were obtained with the soy protein diet. When the percent composition of the particles was determined, both VLDL and LDL had a higher proportion of cholesterol. Turnover studies indicated that the FCRs for radiolabelled VLDL and LDL were reduced in casein-fed animals compared to those fed soy protein. The elevated LDL levels in casein-fed rabbits were primarily due to a reduction in receptor-mediated catabolism of LDL-apo B. Receptor-independent removal in the two groups was similar. These studies show that the hypercholesterolemia in casein-fed rabbits, compared to those fed soy protein, is associated with cholesterol enrichment of LDL and impaired receptor-dependent removal of LDL-apo B.

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The effects of dietary protein sources on plasma cholesterol concentrations are well-documented: animal proteins are hypercholesterolemic relative to plant proteins. While this effect of dietary proteins has been shown in many species, the mechanism is not known. This review will explore the relation between dietary proteins and plasma thyroxine concentrations. Data will be presented showing that feeding dietary animal proteins consistently depresses plasma thyroxine levels. Furthermore, the effects of thyroxine on cholesterol metabolism is consistent with the effects of dietary proteins on cholesterol metabolism. Although evidence is not conclusive, data support the hypothesis that dietary proteins may affect plasma cholesterol levels through changes in plasma thyroxine concentrations. To elucidate the mechanism by which this happens will be the basis for future research.

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Three approaches were employed to identify the amino acid residue(s) that is responsible for the different effects of dietary proteins on the plasma cholesterol level in rats fed cholesterolenriched diets. 1) Experiments on the effects of individual amino acids added to a 25% casein diet showed that sulfur-containing amino acids have the most potent effects on the plasma cholesterol level. Under the dietary conditions used, methionine significantly increased the level of plasma cholesterol while cystine decreased it. It was found that glycine can prevent the methionine-induced enhancement of plasma cholesterol. 2) There was a significant negative correlation between cystine content of dietary proteins and plasma cholesterol levels when animals were fed 7 kinds of animal and plant proteins. 3) Experiments with amino acid mixtures varying in methionine, cystine, and glycine content showed that diets high in methionine and low in cystine and glycine content tend to increase the plasma cholesterol level and diets of opposite amino acid content tend to decrease the plasma cholesterol level. From these results, it was suggested that sulfur-containing amino acids and glycine in dietary proteins are responsible, at least in part, for the alteration of plasma cholesterol level by dietary proteins.

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There were significant differences of postprandial plasma concentrations for 8 amino acids (Cys, Val, Met, Leu, Tyr, Lys, Trp, and Arg) depending on whether pigs consumed a meal containing casein or isolated soy protein. The postprandial plasma amino acid pattern conformed with the amino acid composition of the dietary protein (except for Ser). The data, however, do not allow to conclude unambiguously, whether specific amino acids are responsible for the difference of serum cholesterol following casein or soy protein intake. Significant differences between casein- and soy-fed rats were observed regarding total and free plasma thyroxine and triiodothyronine concentrations. This observation can explain the accompanying different serum cholesterol concentrations. The different thyroid hormone concentrations were not paralleled by differences in TSH levels suggesting that dietary proteins affect thyroid function at the thyroid gland.

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Increased dietary zinc has been shown to reduce plasma total cholesterol in rabbits fed casein. However, the mechanism is not clear. The minerals associated with casein and soya protein are different and present in amounts which can alter the overall mineral composition of the diet. In particular, casein has a much higher ratio of zinc/copper than soy protein. Utilising a range of copper concentrations (2-80μg/g diet) in 14 experiments with casein diets showed a linear relationship between the cholesterolaemic response and copper concentration (when both log transformed) in groups (n=6) of rabbits fed for 12 weeks (r=-0.70, p<0.05). The lower the copper, the greater the response. In no case was the copper content deficient, indicating some interaction must be reducing its availability. Similar analysis utilising the range of zinc (10-125μg/g) in the diets also showed an enhanced response at low intakes (r=-0.85, p<0.05). To elucidate the mechanism, 2 groups of rabbits were fed casein diets containing 21 and 68mg zinc/kg diet for 12 weeks. Low density apolipoprotein B (LDL-apoB) turnover was carried out using ¹²⁵I labelled LDL-apoB and data was fitted to the 2 pool model. The production of LDL-apoB was reduced in animals fed the higher dietary zinc. Zinc appears to act by enhancing the production of LDL-apoB in casein fed animals, perhaps by reducing the availability of copper.

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The present paper shows a series of experiments carried out to elucidate the possible mechanism by which soybean protein isolate (SPI) produces a lower level of plasma cholesterol than casein in rats fed a cholesterol-free diet. When the plasma cholesterol level was in a steady state characteristic of casein and SPI, SPI in the diet was substituted for casein and vice versa. Within 3 days after substitution of dietary protein, the plasma cholesterol level in each group reached a steady state level similar to that in its previous counterpart. The inherent responses of plasma cholesterol to casein and SPI were not changed by the resection of the jejunum or the ileum and the administration of cholestyramine or β-sitosterol. The rates of the sterol synthesis in vivo of the liver and the small intestine were significantly higher in SPI-fed rats than in casein-fed rats. The hypocholesterolemic effect of SPI disappeared when Met was supplemented at a level equivalent to casein. The effects of casein and SPI were reproduced by their equivalent amino acid mixtures. The ratio of the postprandial increment of Met concentration to that of Gly concentration in the portal plasma was significantly higher when casein and its amino acid mixture were fed than when SPI and its amino acid mixture were fed. The casein-induced increase in the level of plasma cholesterol was attributed to an increase in high density lipoprotein (HDL)-cholesterol. HDL-cholesterol concentration showed the positive correlation with the lecithin: cholesterol acyltransferase activity. HDL apolipoprotein level was significantly and the synthetic rate of HDL apolipoproteins in vivo was slightly higher in casein-fed rats than in SPI-fed rats. From all of these observations, the dietary protein-induced alteration of the plasma cholesterol level would arise through the change in HDL metabolism.

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Male Sprague Dawley rats were fed cholesterol-free or cholesterol-enriched purified diets containing 15% protein during 3 weeks. Three animal proteins and 6 plant proteins were used in the diets. Results indicated no specific effect of dietary proteins on serum cholesterol related to their animal or plant origin. Dietary proteins were also subjected to a pepsin-pancreatin in vitro digestion. Significant positive correlations were observed between serum cholesterol of rats fed cholesterol-enriched diets, and the tyrosine content of digestion products. This correlation was higher than that observed with intact dietary proteins. A following study showed that tyrosine supplementation may increase plasma cholesterol when diets contain a protein from which tyrosine is slowly released during enzymatic hydrolysis, indicating a relationship between the availability of dietary amino acids during digestion and plasma cholesterol. It has also been shown that this tyrosine effect was not mediated through plasma thyroid hormones.

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The serum level of cholesterol in rats fed a diet containing soy protein isolate was lower than that in rats fed either casein or rice protein at the level of 15% even after one day feeding, although fecal excretion of bile acids of rats fed soy protein isolate was almost equal with that of rats fed rice protein. Similar effect was also observed in the secretion rate of lipoproteins from the liver. Dietary proteins may affect the synthesis of apolipoproteins directly or through the hormonal system.

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[¹⁴C]Taurocholate was orally administered to rats together with a definite amount of either casein- or soy protein-based diet and its postprandial movement along the digestive tract was investigated. A difference was observed between both dietary groups in intraluminal transit as well as mucosal accumulation of [¹⁴C]taurocholate in the ileum; namely the soy protein intake led to a decrease in the bile acid incorporation into the ileal mucosa relative to the casein intake, although raising its intraluminal stay. In addition, the digestive products from these and other food proteins by pepsin-pancreatin digestion (peptides with molecular weights of more than 1, 000) were examined for their inhibitory effects on in vitro absorption of taurocholate with ileal everted sacs. As the digestive product affinity for taurocholate increased, the rate of taurocholate absorption decreased. It thus seems likely that a food protein more abundant in hydrophobic peptides following intraluminal digestion adsorbs much more bile acids in the gut, thereby disturbing their intestinal absorption.

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The undigested high-molecular weight fraction (HMF) of soybean protein prepared after exhaustive digestion either by microbial proteases or by pepsin exerted a remarkable hypocholesterolemic activity compared to the parent protein in rats fed cholesterol-enriched diets. HMF bound in vitro with bile salts and stimulated fecal excretion of both neutral and acidic steroids far more than did soybean protein. Extraction of HMF with methanol slightly decreased the activity, but the methanol soluble fraction was not regarded as a principle determinant. Further degradation of the methanol-extracted HMF by various proteases resulted in loss of activity. Bile acid binding capacity of HMF from other vegetable proteins was lower than that from soybean protein.

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The effects of the levels (10, 20, and 30%) of dietary proteins, soybean protein or casein, on various lipid parameters were examined in rats. The plasma cholesterol (CHOL) level tended to decrease with an increasing dietary protein level, in particular when diets contained CHOL. The hypocholesterolemic effect of soybean protein was evident with CHOL-enriched diets. The fecal excretion of acidic but not neutral steroids increased with an increasing protein level and it was higher in rats fed soybean protein than in those fed casein. The ratio of arachidonate to linoleate in plasma and liver phosphatidylcholine tended to increase with an increasing dietary protein level, although it was considerably higher in casein than in soybean protein diets. The results indicated that the hypocholesterolemic effect of soybean protein is influenced not only by the amount but also by the presence or absence of dietary CHOL. In addition, the degree of conversion of linoleate to arachidonate also depended on the type and level of dietary protein.

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We have compared the effects of dietary soy protein and casein in diets low in cholesterol (less than 100 mg/d) and in diets enriched in cholesterol (500 mg/d) to examine whether the level of cholesterol intake affects the response of plasma lipoproteins to dietary proteins of plant and animal origin. Normal men and women consumed formula diets containing 20% of calories as soy protein or casein, 27% as fat and 53% as carbohydrate in 2 crossover studies. The dietary periods lasted for 31 days and were separated by a month-long interim period on self-chosen food. Following an initial reduction of plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels on all diets, the plasma lipid and lipoprotein concentrations stabilized. On low-cholesterol diets the concentration of each of the major lipoprotein classes were similar during the soy and the casein dietary periods. On cholesterol-enriched diets, the concentration of LDL-C stabilized at a 16% lower level on soy protein than on the casein diet (p<0.02), while the concentration of high-density lipoprotein-cholesterol (HDL-C) was 16% higher (p<0.01). Since the difference in LDL-C (p<0.05) and in HDL-C (p<0.025) levels on casein and on soy protein diets were significantly greater on the high than on the low cholesterol intake, the findings indicate that the level of dietary cholesterol may determine whether plant and animal dietary proteins have similar or different effects on plasma LDL-C and HDL-C concentrations.

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Effects of additions of amino acids to a 20% casein diet on serum cholesterol (Ch) were studied in hypothyroid and hepatoma-bearing rats with endogenous hypercholesterolemia as well as in normal rats. In normal Wistar rats, methionine (Met) was hypercholesterolemic at the “nutritional” level (0.2-0.4%), but hypocholesterolemic at the “excess” level (1.2-2.4%). In Wistar rats with hypothyroidism induced by thiouracil, the addition of excess (1.2%) Met to the 20% casein diet reduced an endogenous hypercholesterolemia due to hypothyroidism by suppressing an elevation in (VLDL+LDL)-Ch with no significant influence on HDL-Ch. In Donryu rats received a subcutaneous implantation of AH109A cells (an ascites hepatoma line), either 1.2% Met, 1.2% cystine (Cys), or 1.2% Met and 2.5% glycine (Gly) in combination improved a hepatoma-induced hypercholesterolemia and abnormal serum lipoprotein profiles by suppressing a hepatoma-induced increase in (VLDL+LDL)-Ch. From Ch turnover studies in hepatoma-bearing rats, an impaired catabolism of Ch in the liver was suggested to be one cause for the hepatoma-induced elevation in (VLDL+LDL)-Ch. One of the dietary manipulations, Met and Gly in combination (Met+Gly), was found to improve the impaired Ch catabolism, this leading to a reduction of the (VLDL+LDL)-Ch level by Met+Gly in hepatoma-bearing rats.

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The modulating processes of dietary vegetable protein and polyunsaturated fatty acids (PUFAs) on cholesterol (CH) metabolism are very complicated. Since dietary protein can affect PUFA absorption and synthesis through the effects of its amino acid components, the CH-lowering of PUFAs may be modulated by dietary proteins. The effect of dietary PUFAs on the CH-lowering mechanism of vegetable proteins is mainly additive and complementary, but not competitive. Dietrary vegetable protein reduces intestinal CH absorption, enhances catabolism of the CH-carrying lipoproteins, increases the LDL receptor activity, and modulates CH metabolic enzymes through the amino acid-modulated action of hormones. PUFAs may modulate CH metabolism through the action of eicosanoids which modulates the activity of the enzymes responsible for CH metabolism.

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Casein (CAS) promotes desaturation of linoleic acid (LA) in relation to soybean protein (SOY). This protein-effect could be detected within 4 days after feeding different proteins, and persisted even after overnight fasting. The difference was found irrespective of dietary fat even when Δ6-desaturation was depressed by alcohol consumption. The aortic production of prostacyclin (PGI₂) was higher in the CAS group than in the SOY group irrespective of alcohol consumption. When the effect of lysine/arginine (Lys/Arg) ratio of dietary protein on LA desaturation was studied, the addition of Arg to CAS resulted in trend for the proportion of LA to increase and a arachidonic acid (AA) to decrease in liver phosphatidylcholine (PC). However, the effect of Lys addition was inconclusive. Thus, the content of Arg rather than the Lys/Arg ratio was at least one of the factors for the protein-dependent effect.

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The effect of diets enriched with tryptophan (4 and 10 g/kg) on ADP induced platelet aggregation and on plasma lipids was studied with growing rats, following feeding periods of up to 3 weeks. Dietary tryptophan was found to enhance markedly ADP induced platelet aggregation. It appears that this effect was not related to plasma lipid levels. In vitro studies aimed to clarify the mechanism by which tryptophan exerts its action showed that the latter, at concentrations up to 100 μg/ml, had no effect on ADP induced platelet aggregation. On the other hand, serotonin, the metabolic product of tryptophan, increased the ADP induced platelet aggregation in a dose dependent pattern. The possible involvement of serotonin in the observed enhancement of platelet aggregation was further substantiated by the observed high levels of 5-hydroxyindole acetic acid, which is a catabolite of serotonin, in the urine of the experimental animals. It is conceivable that tryptophan enhances platelet aggregation in rats via its metabolite, serotonin, and this may in turn contribute to increased atheroslerotic risk.

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Different aged male rats, 4 weeks or 9 months old, were fed diets containing either casein (CAS), milk whey protein (WHY) or soybean protein (SOY) with corn oil or sardine oil for 4 weeks. The hypocholesterolemic effect of SOY, compared to CAS, was more evident in rats fed corn oil than in those fed sardine oil, and in young rats than in adult rats, irrespective of dietary cholesterol. In contrast, the liver cholesterol-lowering effect of SOY was more marked in adult than in young rats in all experiments. WHY exerted an intermediate effect on the concentration of liver cholesterol. At both ages, the response of liver 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity was diverse and dependent upon the source of dietary fat and age of the animal. Fecal steroid excretion was significantly higher in rats fed SOY than in those fed either CAS or WHY, especially in adult rats. The results showed a diverse interaction of the protein type, fat and age in respect to lipid metabolism.

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August 28 and 29, 1989, a workshop entitled “Dietary protein as a regulator of lipid metabolism” was held in Fukuoka. This workshop highlighted the progress that has been made since 1909, the year that Ignatowski put forward that animal proteins in the diet can induce atherosclerosis in rabbits. It is now clear that humans respond to dietary soybean protein versus animal proteins, such as casein, with a decrease of serum cholesterol concentrations. However, the response in humans is not as pronounced as it is in various animal models. The mechanism by which the type of dietary protein affects serum cholesterol concentrations is still a matter of debate but various elegant concepts have been launched. These concepts have contributed significantly to our current understanding of the regulation of cholesterol metabolism. Future work will concentrate on further unravelling the mechanisms involved, with special reference to proteins other than those used generally, that is soybean protein and casein.

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