Biomedical subjects
Publications and source records attributed to A C Beynen.
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Hepatic cholesterol metabolism was studied in rats fed purified diets supplemented (9% wt/wt) with either fish oil (FO) (n-3 fatty acids) or corn oil (CO) (n-6 fatty acids) for 4 wk. Rats were equipped with permanent catheters in heart, bile duct, and duodenum to allow studies under normal feeding conditions. [3H]-cholesteryl oleate-labeled small unilamellar liposomes, which are rapidly endocytosed by hepatocytes, were intravenously injected to label intrahepatic cholesterol pools, and plasma and bile were collected. FO as compared to CO induced a lowering of plasma cholesterol levels by 38% and of triglyceride levels by 69%. This reduction in plasma lipids in FO rats was accompanied by: (a) an increased bile acid pool size (28%); (b) a fourfold increase in the ratio cholic acid/chenodeoxycholic acid in bile; (c) increased biliary excretion of cholesterol (51%); (d) accelerated excretion of endocytosed free cholesterol into bile; (e) accelerated incorporation of endocytosed cholesterol in bile acids; (f) a significant increase in the bile acid-independent fraction of bile flow; and (g) a threefold increase in hepatic alkaline phosphatase activity. The results show that FO induces changes in transport and metabolic pathways of cholesterol in the rat liver, which result in a more rapid disposition of plasma-derived cholesterol into the bile.
The question addressed was whether preestablished phosphorus (P)-induced nephrocalcinosis would regress after dietary P restriction. Female rats were fed purified diets containing either 0.2% (w/w) P (low P) or 0.6% P (high P). After 29 days, the high-P diet had caused massive nephrocalcinosis as demonstrated chemically (by the analysis of calcium in kidney) and histologically (by inspection of kidney sections stained for calcium phosphate deposits). Switching rats from the high P to the low P diet did not result in a decrease in the degree of nephrocalcinosis within 91 days. Thus, P-induced nephrocalcinosis may not regress upon subsequent P restriction. Rats that had been fed either the 0.2 or 0.6% P diet for 56 days were examined clinically with respect to 14 selected variables. None of the variables discriminated between rats with or without nephrocalcinosis. This might imply that P-induced nephrocalcinosis in female rats does not cause significant discomfort.
In an attempt to assess possible discomfort in rats subjected to orbital puncture while under diethyl-ether anaesthesia, their endocrine stress response was determined. Concentrations of corticosterone, adrenaline and noradrenaline were measured in plasma obtained via a jugular catheter from rats subjected to diethyl-ether anaesthesia with or without orbital puncture. No statistically significant differences were found between the punctured and non-punctured rats as to peak levels of plasma corticosterone and adrenaline as well as for the times required by the increased concentrations to return to baseline values. The rate by which the plasma noradrenaline level returned to baseline values was somewhat decreased by orbital puncture. Diethyl-ether anaesthesia alone produced a marked endocrine response when compared with handling and novelty stress associated with the induction of anaesthesia. It is concluded that diethyl-ether anaesthesia causes pronounced increases in the plasma levels of the selected stress hormones and that orbital puncture does not amplify this response. It is suggested that diethyl-ether anaesthesia masks any effects of orbital puncture.
Massive, toxic doses of vitamin D have been shown to cause nephrocalcinosis in rats, but the effect of this vitamin within its range of fluctuation in commercial rat diets was unknown. Therefore, in two experiments with young female rats, the effect on nephrocalcinosis of a moderately increased level of vitamin D in the diet was studied, that is 5000 IU/kg versus the recommended concentration of 1000 IU/kg. This was done using purified diets with 0.5% (w/w) calcium and 0.04% magnesium containing either 0.2 or 0.6% phosphorus (P). Rats fed the diets containing 0.6% P showed severe kidney calcification compared to those fed the 0.2%-P diets. The level of vitamin D in the 0.2 and 0.6%-P diets did not affect kidney calcification. Bone density was increased after feeding diets containing 5000 instead of 1000 IU of vitamin D/kg. This study suggests that, within 28 days, a moderate increase of the amount of vitamin D in the diet has no influence on the development of kidney calcification. This in turn suggests that the variation in nephrocalcinosis severity and incidence seen in practice in rats fed different commercial diets is unlikely to be related to the different vitamin D concentrations in these diets. However, in rats fed such diets bone metabolism may be influenced differently.
This study addresses the questions to what extent commercial rodent diets would induce nephrocalcinosis, and which dietary components would be responsible for inducing this condition. For this purpose, 10 commercial diets were analysed for selected components and fed to weanling female rats. On the basis of histological inspection of kidney sections, two diets were found to produce significant nephrocalcinosis. The condition could be considered relatively mild because concentrations of Ca in kidney tissue were not increased. There was considerable variation between the commercial diets in the (analysed) concentrations of Ca, P, Mg and protein as well as in the diet-induced urinary pH, urinary volume and caecal weight. Of these parameters, only the dietary Ca:P ratio and group mean urinary pH correlated significantly with the observed variation in group mean calcification scores, the relationships being negative. It is suggested that the Ca:P ratio of commercial rodent diets is an important determinant of nephrocalcinosis.
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The effect of dietary lactose, when compared with glucose, on phosphorus-induced nephrocalcinosis was studied in young, female rats. Nephrocalcinogenic diets containing either 0.4 or 0.6% (w/w) phosphorus were used, and lactose was added up to concentrations of 30%. The diets were fed for 28 days. The 0.4 and 0.6% phosphorus diets, when compared with a diet containing 0.2% phosphorus, caused mild and severe kidney calcification, respectively; kidney calcification was demonstrated chemically by the analysis of kidney calcium, and histologically by staining kidney slides for calcium deposits. Dietary lactose caused calciuria, decreased urinary pH and increased cecum weights. The addition of lactose to the diet partly counteracted nephrocalcinogenesis induced by diets containing 0.4% phosphorus, but it did not influence the severity of nephrocalcinosis seen in rats fed diets containing 0.6% phosphorus. It is suggested that high amounts of lactose in the diet have only weak anti-nephrocalcinogenic activity.
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The question addressed is whether the amount of dietary fat rather than that of carbohydrates or protein affects esterase-1 (ES-1) activity in plasma of rats. For this purpose, the effects on plasma ES-1 activity of replacement of dietary fat, by isocaloric amounts of either carbohydrates or protein were studied in male rats. In rats fed high-fat diets, corn oil induced higher plasma ES-1 activities than coconut fat. Plasma ES-1 activity was decreased by a decrease in fat intake. Replacement of fat by carbohydrates produced a similar decrease of plasma ES-1 activity as did replacement of fat by protein. Replacement of carbohydrates by protein did not significantly change plasma ES-1 activity. It is concluded that the amount of fat in the diet specifically influences ES-1 activity in plasma.
We studied the effects of dietary fats, especially fish oil, on the activities of esterase-1 (ES-1) and butyrylcholinesterase in the plasma of rats. The identification of nutritional determinants of these enzymes could provide clues as to their physiological function. Fish oil, when compared with corn oil, consistently caused increased activities of both enzymes. Plasma ES-1 activity, but not butyrylcholinesterase activity, was increased after isocaloric replacement of carbohydrates by coconut fat. Dietary medium-chain triglycerides, when compared with corn oil, produced decreased and increased activities of butyrylcholinesterase and ES-1, respectively. Various plant fats, such as corn oil, linseed oil, coconut fat, palm oil, palm kernel oil, soybean oil and rapeseed oil, did not differentially influence butyrylcholinesterase activities. Plasma triglyceride concentrations were lowered by fish oil and increased by coconut fat and palm kernel oil. For individual rats in 5 out of 6 experiments, weak, negative correlation coefficients of the order of 0.3 were found between the changes in plasma butyrylcholinesterase activities and in plasma triglyceride concentrations.
The effect in rabbits of giving isonitrogenous purified diets containing casein, ovalbumin, fish protein, milk-whey protein and soya-bean protein were compared. The diets were balanced for cholesterol and for the amount and type of fat. When incorporated into low-cholesterol diets (0.08 g cholesterol/kg), casein, ovalbumin and soya-bean protein produced similar levels of serum cholesterol. With a high background of dietary cholesterol (1.5 g/kg), serum cholesterol concentrations increased with soya-bean protein, whey protein, casein and fish protein, in that order. Thus, the hypercholesterolaemic effect of casein in carefully balanced diets was only seen against a high-cholesterol background. The development of hypercholesterolaemia produced by giving fish protein was different from that produced by casein. First, less cholesterol accumulated in the very-low-density-lipoprotein fractions and more in the lipoproteins of higher density with fish protein than with casein. Second, fish protein, unlike casein, did not increase liver cholesterol. Third, transfer of rabbits from a diet containing soya-bean protein to one containing casein resulted in an immediate marked depression in neutral steroid and bile acid excretion in faeces. However, when rabbits were fed on the diet with fish protein after the diet with soya-bean protein, there was no significant depression in neutral steroid output and the depression in bile acid output was delayed. The present study suggests that different animal proteins cause hypercholesterolaemia by different mechanisms.
Swine fitted with re-entrant ileo-cecal cannulas were fed purified diets containing either casein or soybean protein to study possible relations between cholesterol metabolism, digestion of dietary constituents and postprandial patterns of various serum components. Compared with soybean protein, dietary casein produced an increase in serum total cholesterol in which the excess cholesterol was located in the low density lipoprotein fraction. Ileal and fecal excretion of neutral steroids was diminished in pigs fed casein, suggesting that cholesterol absorption was stimulated. The apparent ileal absorption of protein was increased in pigs fed casein. The enhanced absorption of cholesterol and protein was associated with a reduced rate of flow of chyme through the ileum. The output of bile acids in the feces of pigs fed casein was decreased, whereas the ileal output was not significantly affected. This could be attributed to increased uptake of bile acids from the cecum and/or colon, which may in part be related to the indirectly observed decreased formation of secondary bile acids. Postprandial serum concentrations of insulin and glucose were temporarily increased in pigs fed casein, whereas those of triglycerides were decreased. We suggest that the decreased excretion of cholesterol and bile acids is the major determinant of casein-induced hypercholesterolemia in swine.
This study was carried out to test the hypothesis that diet-induced nephrocalcinosis causes enhanced loss of albumin in urine, irrespective of the composition of the nephrocalcinogenic diet. Female rats were fed various purified diets for 28 days. There was a control diet (0.5% Ca, 0.04% Mg, 0.4% P, 15.1% protein, wt/wt), a low Mg (0.01% Mg), a high protein (30.2% protein) and a high P diet (0.6% P). The low Mg and high P diet induced nephrocalcinosis as demonstrated histologically and by markedly increased concentrations of kidney Ca. In rats fed the high protein diet, nephrocalcinosis was essentially absent. Group mean values of urinary excretion of albumin and plasma concentrations of urea were increased in rats fed either the low Mg or high P diet. The high protein diet did not affect urinary albumin but caused lysozymuria which was not seen in the other groups. Plasma urea was increased in rats fed the high protein diet. In individual rats, the concentration of Ca in kidney and urinary albumin excretion were positively correlated. It is suggested that nephrocalcinosis in female rats induced by either low Mg or high P intake causes kidney damage which in turn leads to increased concentrations of albumin in urine and urea in plasma.
We describe a method for the isolation and recirculating perfusion of rabbit livers. Livers were perfused simultaneously through the portal vein and the hepatic artery. Precise descriptions of the surgical preparation, perfusion apparatus and perfusion method are given. The viability of rabbit livers was assessed with the use of physiological, biochemical and histological parameters. We conclude that the isolated perfused rabbit livers are sufficiently viable to study their short-term metabolism.
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.
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.