The effects of fibrates and statins as drugs for the treatment of dyslipidemias are well described in the literature and their mechanisms of action practically established [21, 23]. The action of these compounds is associated with transcriptional control of triglycerides metabolism by the activation of the transcription factor PPAR-α (peroxisome proliferator-activated receptor) and consequent induction of the enzymes of β-oxidation of fatty acids in mitochondria. Statins inhibit endogenous cholesterol synthesis by inhibition of 3-hydroxy-3-methyl-glutamyl-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Depending on which generation of statin is used the various doses lead to reductions of LDL-C (low-density lipoprotein cholesterol) in a range between 20 and 60% . Diet components, such as plant sterols/stanols, soluble fibers, omega-3-fatty acids, niacin and soybean components; have been combined with a variety of drugs, in experiments in vitro and in vivo, to treat dyslipidemia .
In our experiment, the differences in body weight gain between groups were not significant, although the weights of the livers of rats consuming the mixture of drugs and 7S-FF were much higher than those of other groups. The group that received rosuvastatin had a liver weight gain lower than those given fenofibrate. The observed increase in liver weight by administration of fenofibrate is reported in the literature. Yamamoto et al.  found such an increase on administering fenofibrate at 0.05% in diet of rats, while, Mancini et al.  observed an increase of 30.2% in the liver weight of hyperlipidemic rats after daily administration of 320 mg.kg-1 of fenofibrate for 120 days. Ji et al.  observed an increase in the liver weight of the animals fed on a hyperlipidemic diet and treated with atorvastatin at a dose of 30 mg.kg-1 day-1 for 8 weeks; the authors also showed an increase in the hepatosomatic index of these animals. These results are consistent with published reports of liver hypertrophy after fenofibrate administration, due to proliferation of peroxisomes and mitochondria. In our study, the raised hepatosomatic index of the animals that received fenofibrate thus resulted from the high liver weight and the insignificant body weight gains of the animals (Table 2 and 3). The protein-drug combination caused reductions of 16 and 16.7% in the hepatosomatic indices of the animals that ingested fenofibrate and rosuvastatin, respectively, and in the latter case practically annulled the effect of the drug alone. Therefore, the β-conglycinin was able to reverse the increase in the liver weight and hepatosomatic index of the animals that ingested rosuvastatin, but not those of the 7S+FF animals.
The protein β-conglycinin has been studied for its effects on dyslipidemia, both as a single protein added to the diet, and as a daily dose [7, 8, 10, 12–14, 37, 38], and in both cases distinct effects on lipid metabolism were observed. Studies using animals subjected to a daily dose of β-conglycinin [13–15], and our study, show that the 7S protein has an effect comparable to that of rosuvastatin, but weaker than fenofibrate, in reducing levels of total cholesterol. Surprisingly, the β-conglycinin/rosuvastatin combination raised the total cholesterol to a higher level than in any other group, even the hypercholesterolemic group, while the combination with fenofibrate led to lower values of TC than either separately.
The LDL-C/HDL-C ratio is used as risk factor for coronary heart diseases (CHD), on account of the effect of each fraction on the atherosclerotic process . Thus, the atherogenic index (AI) of the hypercholesterolemic diet group (HC), in this experiment, was 8 times higher than that of rats on the casein standard diet , as also observed by other authors . All treatments resulted in reductions in AI of the animals, the combination of 7S protein and fenofibrate (HC+7S+FF group) being the most efficient, followed by fenofibrate (HC+FF group), protein (HC+7S group), protein plus rosuvastatin (HC+7S+RO group) and rosuvastatin (HC+RO group), with falls of 81, 76, 57, 55 and 50%, relative to HC, respectively (Table 4). These data indicate that the protein-fenofibrate and protein-rosuvastatin combinations resulted in lower cardiovascular risks than did the drugs alone (Table 4). Even though the combination of protein with rosuvastatin rose the level of total cholesterol approximately to that observed in the group HC, the combination reduced the cardiovascular risk by increasing the HDL-C fraction (Table 4).
The mechanisms of action of these drugs are properly established, as mentioned above. However, the mechanisms of action of soybean proteins on lipid metabolism are not yet clear, as various studies point to different actions, such as increasing the amount of LDL-receptors [7, 8, 40, 41], inhibiting HMG-CoA reductase , sequestering bile acids , activiting β-oxidation related enzymes [38, 43], gene expression [40, 43] and others [11, 12, 38, 41]. However, a lot of evidence suggests that the effects of soybean proteins could be due to biologically active peptides produced by digestion of the proteins in the gastrointestinal tract, and that these peptides would be the main agents affecting cholesterol and triacylglyceride metabolism, since the protein itself cannot be absorbed intact.
The behaviors of these combinations suggest a possible synergy between the protein and fenofibrate and an antagonistic effect with rosuvastatin, in relation to serum total cholesterol. Although, in the case of rosuvastatin, the increase in the HDL-C fraction to a level above that with the protein or drug alone may be due to a higher rate of cholesterol catabolism, an important function of this fraction is as a carrier of cholesterol to the liver. Fenofibrate has been characterized as a drug that causes an increase in HDL-C levels , while the literature indicates only a slight modification of this fraction by the statins, unrelated to dose . These observations were confirmed by our experiment, but β-conglycinin had a positive effect in combination with rosuvastatin, resulting in a higher increase than with the drug alone. The non-HDL-C levels followed the same trend as total cholesterol. The combinations of protein with the drugs did not affect the TG levels, although the rosuvastatin improved the action of the protein in the combination and reduced the level compared to the drug alone.
The liver cholesterol concentration was reduced by all treatments, relative to HC, the greatest reduction (37%) being seen in the HC+RO group. Nevertheless, 7S-rosuvastatin combination annulled the effect of the drug, showing the same value as the protein alone and much higher than with the drug alone. The 7S-fenofibrate combination resulted in a fall in concentration of hepatic triacylglycerides, relative to HC and to the drug alone (which led to a rise in this level), to the same concentration as HC+FF. However, the fenofibrate, without or with 7S protein, maintained the hepatosomatic index above that of the HC group, due to the appreciable increase in the liver weight of the animals.
The meta-analysis of studies by Anderson et al.  demonstrated a 12.5% reduction in the levels of LDL-C for 1.5 to 2 oz of soy protein daily (50 g/d), whereas a recent meta-analysis reported only 4-6% . More recently, Jenkins et al.  discussed the effect of cholesterol reduction by soy proteins in light of a review of claims for heart health by the U.S. FDA and a meta-analysis of studies on the action of soy protein; they concluded that soy remains one of the few food components that reduce serum cholesterol when added to the diet. Results in the literature show that soybean protein, when used as the only protein source in the diet affects these serum parameters in various ways, depending on the experimental model, animal, dose and other factors . However, when administered as a daily dose in hypercholesterolemic animals fed a standard casein diet, enriched by cholesterol and cholic acid, it had the effect of reducing TC, LDL-C and TG levels in a dose-dependent manner [13, 14]. It is important to note that in our study the β-conglycinin was administered by gavage, alone and/or in combination with the drugs at a concentration equivalent to 2.75-2.90% of the daily total protein intake, and that the doses were given separately to the animals, with a difference of 6 hours between drug and the protein. The fact that the β-conglycinin was isolated may be the cause of its higher effect on the cholesterol metabolism relative to the total protein or soybean protein products. We may note that, despite the use of various experimental models with different in vitro and in vivo approaches, the mechanism of action of soy protein on lipid metabolism is still controversial and deserves further study, especially in relation to its interactions with drugs of similar effect. At the moment, studies to reveal the mechanism of action of β-conglycinin, alone and combined with statins are in progress in our lab.