Metabolic adjustments in normal and diabetic pregnancy.
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Biomedical subjects
Publications and source records attributed to J R Li.
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The effects of probucol treatment on cholesterol metabolism were examined in rats. Male Sprague-Dawley rats were divided into 3 groups: one group was given 0.25% probucol containing chow diet, one group was given 0.25% clofibrate containing chow diet, and the third group was fed chow diet alone. All groups of rats were maintained on these regimens for 4 weeks before killing. Probucol treatment resulted in a decrease in plasma cholesterol and cholesterol 7 alpha-hydroxylase activity. Clofibrate treatment resulted in a reduction of plasma cholesterol, hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities. The fecal excretion of neutral and acidic sterols were decreased significantly in the probucol or clofibrate-treated rats. In the bile there was a decrease in the concentration of total bile acids. These results suggest the mechanism for hypocholesterolemic action of probucol to be different from that of clofibrate.
Effects of carbon monoxide, nitrogen, ferricytochrome c and p-hydroxymercuribenzoate were studied on cholesterol 7 alpha-hydroxylase activity of swine hepatic microsomes. The results suggest that a microsomal electron transport system is involved in hepatic microsomal cholesterol 7 alpha-hydroxylation in swine. Cholesterol 7 alpha-hydroxylation is inhibited by superoxide dismutase in the standard assay system containing a NADPH generating system. Superoxide dismutase also inhibited cholesterol 7 alpha-hydroxylation in the system where superoxides were generated by enzymatic or nonenzymatic means in the absence of NADPH-generating system. The current study suggests that superoxide anion may be an important factor in the cholesterol 7 alpha-hydroxylation of swine.
Experiments were designed to study whether or not the mechanism of handling dietary cholesterol in adulthood can be modulated by the manipulation of cholesterol homeostasis during neonatal period. The effects of enhancing cholesterol degradation (cholestyramine feeding), high dietary cholesterol intake, and early weaning during neonatal period of guinea pigs on their subsequent plasma cholesterol levels and the response to dietary cholesterol challenged in adulthood were investigated. Pretreatment of neonatal guinea pigs with cholestyramine resulted in (a) a lower plasma cholesterol level, (b) an increased excretion rate of fecal bile acids and total steroids, (c) an expanded bile acid pool, (d) an increased activity of cholesterol 7 alpha-hydroxylase, and (e) no change in the hepatic 3-hydroxy-3-methylglutaryl coenzyme A (CoA) reductase activity when challenged with cholesterol in adulthood. Cholesterol pretreatment during neonatal period resulted in (a) no alteration in the plasma cholesterol level, (b) no alteration in the fecal excretion of steroids, or (c) no alteration in the cholesterol 7 alpha-hydroxylase activity when they were challenged with a high cholesterol diet. Early weaning did not influence the fecal excretion of steroids or cholesterol 7 alpha-hydroxylase activity but resulted in a slight decrease in the hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity when they were challenged with a high cholesterol diet. These results suggest that stimulation of cholesterol catabolism rather than cholesterol feeding or early weaning during neonatal period can influence the response to dietary cholesterol challenge in adulthood.
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A genetically hypercholesterolemic strain of rats was selectively bred, starting from an ordinary albino mutant of Rattus norvegicus. The new strain was given the designation RICO, standing for rats with increased cholesterol. In these animals, hypercholesterolemia is established, in both sexes, one day after weaning, and it increases progressively thereafter. It is due to elevated concentrations of LDL- and HDL-cholesterol. As in the ordinary rat, the HDL fraction makes up the main part of the serum cholesterol in the RICO rat. Metabolic studies revealed that in the RICO strain the overall rate of hepatic cholesterol synthesis is accelerated, as a result of higher than normal activity of 3-hydroxy-3-methylglutaryl-CoA reductase. The activity of cholesterol-7 alpha-hydroxylase is decreased in RICO rats, indicating a lower than normal rate of cholesterol catabolism. No difference was found between RICO and ordinary rats with respect to fecal excretion of bile acids and cholesterol.
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The effect of feeding cholestyramine to neonatal guinea pigs on their subsequent plasma cholesterol levels and response to dietary cholesterol were studied. Male neonatal guinea pigs were suckled for 6 days. One group was maintained on a 1.1% cholestyramine diet for 6 weeks and the control group weaned normally. Both groups of guinea pigs were then fed a standard diet of Guinea Pig Chow for 6 weeks. During the standard diet period bile acid and neutral sterol excretion rates were significantly higher in the group previously treated with cholestyramine than the control group despite the similarity in plasma cholesterol levels. When both groups of guinea pigs were subjected to a 0.5% cholesterol diet for 4 weeks, plasma cholesterol levels were significantly lower in the group previously treated with cholestyramine than the control group. The plasma cholesterol levels continued to be significantly lower in the group previously treated with cholestyramine after an additional four weeks on standard diet. These results suggest that stimulation of cholesterol catabolism in the neonatal period can influence the subsequent response to dietary cholesterol.
The relationship of the changes in plasma cholesterol to bile acid pool was studied in the newborn guinea pig. Plasma cholesterol reached the maximum on the fifth day and gradually declined to adult levels. The cholesterol concentration in the high density lipoproteins (HDL) was higher in the newborn guinea pig than in the adult. Plasma triglycerides peaked on the third day and decreased markedly. The bile acid pool increased progressively after birth with a 13-fold increase at 5 days of age. While the hepatic triglycerides decreased sharply in the newborn guinea pig, hepatic cholesterol increased in the first 5 days and then decreased to adult levels. This study has described the occurrence of "neonatal hypercholesterolemia" in the guinea pig and its possible relationship to the low level of bile acid synthesis.
Optimal assay conditions for cholesterol 7 alpha-hydroxylase activity in swine liver microsomes were determined. The enzyme activity is induced three-fold by feeding cholestyramine to the swine. This suggests that cholesterol 7 alpha-hydroxylase is likely to be the rate-limiting enzyme for biosynthesis of bile acids in swine. The effects of various bile acids on cholesterol 7 alpha-hydroxylase in swine microsome and "solubilized" cholesterol 7 alpha-hydroxylase activity have been studied. There is no significant reduction of native microsomal enzyme activity. However, except for chenodeoxycholic acid, most of the bile acids tested exerted significant inhibition on "solubilized" cholesterol 7 alpha-hydroxylase. This finding suggests that bile acids could interact with and regulate the rate-limiting enzyme for bile acid formation in swine.
Optimal assay conditions for hepatic HMG-CoA reducatase activity and cholesterol 7 alpha-hydroxylase activity in the guinea pig were determined. These two enzyme activities were studied in the liver of newborn guinea pigs during the first three postnatal weeks. Hepatic HMG-CoA reductase activity of neonatal guinea pigs was similar to that of adult animals. However, cholesterol 7 alpha-hydroxylase activity of newborns was about one-third of that in adult guinea pigs. This finding suggests that the system for bile acid synthesis in the neonatal guinea pigs is underdeveloped.
The effects of cholestyramine feeding on biliary ursodeoxycholic acid, fecal excretion of bile acids and neutral sterols on cholesterol 7 alpha-hydroxylase and hepatic HMG-CoA reductase were examined in the guinea pig. In the bile there was a 57% decrease in the concentration of ursodeoxycholic acid while an increase was observed in the concentration of chenodeoxycholic acid. Cholestyramine feeding for ten days resulted in a decrease in plasma cholesterol levels and an increase in both hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities. The fecal excretion of both bile acids and neutral sterols was significantly increased.
The relationship of bile acid and cholesterol excretion to changes in plasma cholesterol during pregnancy were studied in guinea pigs. Plasma cholesterol level increased in the first trimester of pregnancy, reached to a peak during the second trimester and decreased in the third trimester reaching the lowest level at one week prior to parturition. Cholesterol level returned to the control level after parturition. Plasma triglyceride level followed a similar trend attaining peak values at second trimester and gradually returned to the control level at the third trimester of pregnancy. Bile acid and total sterol excretion were significantly higher in guinea pigs during the last phase of pregnanccy while they remained unchanged during early stage of pregnancy.
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