Differential effects of polyunsaturated fatty acids on sterol synthesis rates in adult and fetal tissues of the hamster: consequence of altered sterol balance

Cholesterol is necessary for the proper growth and development of the fetus. Consequently, disruptions in cholesterol biosynthesis lead to abnormal fetal development. It has been shown that in cells exposed to polyunsaturated fatty acids (PUFA), the expressions of genes and activities of enzymes involved in cholesterol synthesis are reduced. Similarly, we found that adult male hamsters fed PUFA-enriched diets had an approximately 60% reduction in in vivo hepatic sterol synthesis rates. If fetal tissues respond to PUFA in the same manner as do adult livers, then maternal dietary PUFA could lead to a reduction in fetal sterol synthesis rates and possibly abnormal development. To investigate the impact of maternal dietary fatty acids on fetal sterol synthesis rates, female hamsters were fed diets enriched in various fatty acids before and throughout gestation. In vivo sterol synthesis rates were measured in fetuses at mid- and late gestation. At both gestational stages, dietary PUFA had no effect on fetal sterol synthesis rates. This lack of effect was not a consequence of a lack of PUFA enrichment in fetal fatty acids or the lack of PUFA receptor expression in the fetus. We hypothesize that the fetus may experience a dysregulation of sterol synthesis as the result of the fetus being in a negative sterol balance; the PUFA-induced suppression of sterol synthesis in the adult male hamster liver was ablated by creating a net negative sterol balance across the adult hepatocyte.     

Effect of maternal hypercholesterolemia on fetal sterol metabolism in the Golden Syrian hamster.

The fetus obtains a significant amount of cholesterol from de novo synthesis. Studies have suggested that maternal cholesterol may also contribute to the cholesterol accrued in the fetus. Thus, the present studies were completed to determine whether diet-induced maternal hypercholesterolemia would affect fetal sterol metabolism. To accomplish this, maternal plasma cholesterol concentrations were increased sequentially by feeding hamsters 0.0%, 0.12%, 0.5%, and 2.0% cholesterol. At 11 days into a gestational period of 15.5 days, cholesterol concentrations and sterol synthesis rates were measured in the three fetal tissues: the placenta, yolk sac, and fetus. In the placenta and yolk sac, the cholesterol concentration increased significantly when dams were fed as little as 0.12% cholesterol (P < 0.0167), and sterol synthesis rates decreased in dams fed at least 0.5% or 2% cholesterol, respectively (P < 0.0167). In the fetus, changes in fetal cholesterol concentration and sterol synthesis rates occurred only when dams were fed at least 0.5% cholesterol, which corresponded to a greater than 2-fold increase in maternal plasma cholesterol concentrations. When the cholesterol concentration in the fetal tissues in each animal was plotted as a function of maternal plasma cholesterol concentration, a linear relationship was found (P < 0.001).These studies demonstrate that sterol homeostasis in fetal tissues, including the fetus, is affected by maternal plasma cholesterol concentration in a gradient fashion and that sterol metabolism in the fetus is dependent on sterol homeostasis in the yolk sac and/or placenta.     

Effects of cortisol or corticotropin administration on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and plasma lipids in the pregnant rat and fetuses

Pregnant rats were given pharmacological doses of cortisol or ACTH or no hormone from gestation day 9 to 19 and maternal and fetal hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and plasma cholesterol studied on gestation day 20. Reductase activity was also studied in the maternal and fetal adrenal of the rats given cortisol or no hormone. Cortisol administration increased the maternal and fetal plasma cholesterol but had no effect on the hepatic active (phosphorylated) 3-hydroxy-3-methylglutaryl-CoA reductase activity when compared to untreated rats. Total (active + inactive) 3-hydroxy-3-methylglutaryl-CoA reductase activity, however, was reduced in maternal liver but not altered in the fetal liver by cortisol. The maternal cortisol treatment decreased the fetal, but not maternal, adrenal 3-hydroxy-3-methylglutaryl-CoA reductase total enzyme activity. The data support a hypothesis that utilization of plasma cholesterol for adrenal steroidogenesis may be an important determinant of plasma cholesterol homeostasis in the rat fetus. Maternal ACTH administration increased the foetal but not maternal plasma cholesterol, whilst active 3-hydroxy-3-methylglutaryl-CoA reductase activity was increased in the pregnant rat but not her fetuses. This result may suggest coordination of hepatic active reductase activity with adrenal cholesterol utilization in the pregnant rat. The reason for the fetal hypercholesterolaemia caused by ACTH, which is not known to cross the placenta, is uncertain. The studies, however, indicate that fetal cholesterol homeostasis and the rate limiting enzyme of cholesterol synthesis is influenced by maternal glucocorticoid administration.     

Chronic maternal feed restriction impairs growth but increases adiposity of the fetal guinea pig

Small size at birth has been associated with an increased risk of central obesity and reduced lean body mass in adult life. This study investigated the time of onset of prenatally induced obesity, which occurs after maternal feed restriction, in the guinea pig, a species that, like the human, develops substantial adipose tissue stores before birth. We examined the effect of maternal feed restriction [70% ad libitum intake from 4 wk before to midpregnancy, then 90% until day 60 gestation (term approximately 69 days)] on fetal growth and body composition in the guinea pig. Maternal feed restriction reduced fetal (-39%) and placental (-30%) weight at 60 days gestation and reduced liver, biceps muscle, spleen, and thymus weights, relative to fetal weight, while relative weights of brain, lungs, and interscapular and retroperitoneal fat pads were increased. In the interscapular depot, maternal feed restriction decreased the volume density of multilocular fat and increased that of unilocular fat, resulting in an increased relative weight of interscapular unilocular fat. Maternal feed restriction did not alter the relative weight of perirenal fat or the volume density of adipocyte populations within the depot but increased unilocular lipid locule size. Maternal feed restriction in the guinea pig is associated with decreased weight of major organs, including liver and skeletal muscle, but increased adiposity of the fetus, with relative sparing of unilocular adipose tissue. If this early-onset obesity persists, it may contribute to the metabolic and cardiovascular dysfunction that these offspring of feed-restricted mothers develop as adults.     

Ontogeny of microsomal activities of triacylglycerol synthesis in guinea pig liver

Because the onset of triacylglycerol-rich lipoprotein synthesis occurs in guinea pig liver during fetal life, we investigated the microsomal enzyme activities of triacylglycerol synthesis in fetal and postnatal guinea pig liver. Hepatic monoacylglycerol acyltransferase specific and total microsomal activities peaked by the 50th day of gestation and declined rapidly after birth to levels that were virtually unmeasurable in the adult. Peak fetal specific activity was more than 75-fold higher than observed in the adult. The specific activities of fatty acid CoA ligase and lysophosphatidic acid acyltransferase increased 2- to 3-fold before birth; lysophosphatidic acid acyltransferase increased a further 2.6-fold during the first week of life. Specific activities of phosphatidic acid phosphatase, microsomal glycerophosphate acyltransferase, and diacylglycerol acyltransferase varied minimally over the time course investigated. These data demonstrate that selective changes occur in guinea pig hepatic microsomal activities of triacylglycerol synthesis before birth. Because of an approximate 11-fold increase in hepatic microsomal protein between birth and the adult, however, major increases in total microsomal activity of all the triacylglycerol synthetic activities occurred after birth. The pattern of monoacylglycerol acyltransferase specific and total microsomal activities differs from that of the rat in occurring primarily during the last third of gestation instead of during the suckling period. This pattern provides evidence that hepatic monoacylglycerol acyltransferase activity probably does not function to acylate 2-monoacylglycerols derived from partial hydrolysis of diet-derived triacylglycerol.     

Maternal selenium deficiency increases hydrogen peroxide and total lipid peroxides in porcine fetal liver

To investigate the role of selenium (Se) in the developing porcine fetus, prepubertal gilts (n=42) were randomly assigned to either Se-adequate (0.39 ppm Se) or Se-deficient (0.05 ppm Se) gestation diets 6 wk prior to breeding. Maternal and fetal liver was collected at d 30, 45, 70, 90, and 114 of pregnancy. Concentrations of Se in maternal liver decreased during gestation in gilts fed the low-Se diet. The activity of cellular glutathione peroxidase (GPx) was decreased at d 30 and 45 of gestation in liver of gilts fed the low-Se diet. Concentrations of malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) were greater in liver homogenates from gilts fed the low-Se diet. Within the fetuses, liver Se decreased in those fetuses of gilts fed the low-Se diet. Although the activity of GPx in fetal liver was not affected by the maternal diet, concentrations of H₂O₂ and MDA in fetal liver were greater in fetuses from gilts fed the low-Se diet. Maternal liver GPx activity was approx 12-fold greater than fetal liver GPx activity regardless of dietary treatment. These results indicate that maternal dietary Se intake affects fetal liver Se concentration and feeding a low-Se diet during gestation increases oxidative stress to the fetus, as measured by fetal liver H₂O₂ and MDA.     

No effect of chronic ethanol administration on the activity of alcohol dehydrogenase and aldehyde dehydrogenases in the near-term pregnant guinea pig

The objective of this study was to determine the effect of chronic maternal administration of moderate-dose ethanol on alcohol dehydrogenase, low Km aldehyde dehydrogenase, and high Km aldehyde dehydrogenase activities in the guinea pig at near-term pregnancy. The activity of each enzyme in the maternal liver, fetal liver, and placenta of the guinea pig at 59 days of gestation (term, 66 days) was determined spectrophotometrically following chronic daily oral administration of two doses of 1 g ethanol/kg maternal body weight or isocaloric sucrose solution. There was no experimental evidence of ethanol-induced malnutrition in the mother or growth retardation in the fetus. There was a statistically significant increase (65%) in the microsomal cytochrome P-450 content of the maternal liver for the ethanol treatment compared with the sucrose treatment. The alcohol dehydrogenase, low Km aldehyde dehydrogenase, and high Km aldehyde dehydrogenase activities in the maternal liver, fetal liver, and placenta were not statistically different for the ethanol-treated compared with the sucrose-treated animals. This also was the case for the maternal blood and fetal blood ethanol and acetaldehyde concentrations, determined at 2h after maternal administration of 1 g ethanol/kg maternal body weight. These data demonstrate that the ethanol- and acetaldehyde-oxidizing enzyme activities in the maternal-placental-fetal unit of the guinea pig at near-term pregnancy were not changed by chronic administration of moderate-dose ethanol.     

Effects of cholestyramine feeding on tissue lipase activities and plasma fatty acids in the pregnant rat

Rats fed a non-absorbable bile acid binding resin (cholestyramine) throughout gestation had decreased activities of adipose tissue lipoprotein lipase (LPL), hepatic triacylglycerol lipase and a heparin-releasable placental lipase distinct from LPL, when assayed at near-term gestation. The fetal plasma and liver triacylglycerol concentrations were not altered. The fetal liver total lipid and plasma triacylglycerol, however, had reduced levels of n-6 and n-3 series fatty acids, suggesting decreased availability of maternal dietary-derived essential fatty acids. These studies suggest that cholestyramine feeding may alter triacylglycerol flux and the quantity or type of maternal fatty acids available for placental transfer. The resin has application for in vivo study of the effects of maternal lipid transfer on the regulation of fetal hepatic lipid synthesis.     

Maternal high density lipoproteins affect fetal mass and extra-embryonic fetal tissue sterol metabolism in the mouse

Previous studies have shown that antibodies to cubulin, a receptor on the yolk sac that binds high density lipoproteins (HDL) and cobalamin, induce fetal abnormalities. Mice with markedly low concentrations of plasma HDL-cholesterol (HDL-C) give birth to healthy pups, however. To establish whether maternal HDL-C has a role in fetal development, sterol metabolism was studied in the fetus and extra-embryonic fetal tissues in wild-type and apolipoprotein A-I-deficient mice (apoAI-/-). Maternal HDL-C content was markedly greater in apoAI+/+ mice prior to pregnancy and at 13 days into gestation. By 17 days into gestation, HDL-C content was similar between both types of mice. Fetuses from apoAI (-/- x -/-) matings were 16;-25% smaller than control mice at 13 and 17 days of gestation and contained less cholesterol. The differences in size and cholesterol content were not due to a lack of cholesterol synthesis or apoA-I in the fetus. In the yolk sac and placenta, sterol synthesis rates were approximately 50% greater in the 13-day-old apoAI-/- mice as compared to the apoAI+/+ mice. Even though synthesis rates were greater, cholesterol concentrations were 22% lower in the yolk sac and similar in the placenta of apoAI-/- mice as compared to tissues of wild-type mice. These data suggest that a difference in maternal HDL-C concentration or composition can affect the size of the fetus and sterol metabolism of the yolk sac and placenta in the mouse.     

Effect of an enriched cholesterol diet during gestation on fatty acid synthase, HMG-CoA reductase and SREBP-1/2 expressions in rabbits

Pregnancy is associated with hyperlipidemia and hypercholesterolemia in humans. These changes take place to support fetal growth and development, and modifications of these maternal concentrations may influence lipids and cholesterol synthesis in the dam, fetus and placenta. Administration of a 0.2% enriched cholesterol diet (ECD) during rabbit gestation significantly increased cholesterol and triglyceride (TG) levels in maternal livers and decreased fetal weight by 15%. Here we used Western blot analysis to examine the impact of gestation and 0.2% ECD on the expression levels of fatty acid synthase (FAS), HMGR and SREBP-1/2, which are involved in either lipid or cholesterol synthesis. We confirmed that gestation modifies the hepatic and circulating lipid profile in the mother. Our data also suggest that the maternal liver mainly supports lipogenesis, while the placenta plays a key role in cholesterol synthesis. Thus, our data demonstrate a decrease in HMGR protein levels in dam livers by feeding an ECD. In the placenta, SREBPs are highly expressed, and the ECD supplementation increased nuclear SREBP-1/2 protein levels. In addition, our results show a decrease in FAS protein levels in non-pregnant liver and in the liver of offspring from ECD-treated animals. Finally, our data suggest that the placenta does not modify its own cholesterol synthesis in response to an increase in circulating cholesterol. However, the dam liver compensates for this increase by essentially decreasing the level of HMGR expression. Because HMGR and FAS expressions do not correlate with the circulating lipid profile, it would be interesting to find which genes are then targeted by SREBP-1/2 during gestation.     

Gestational changes in concentrations of selenium and zinc in the porcine fetus and the effects of maternal intake of selenium

The effect of maternal dietary selenium (Se) and gestation on the concentrations of Se and zinc (Zn) in the porcine fetus were determined. Mature gilts were randomly assigned to treatments of either adequate (0.39 ppm Se) or low (0.05 ppm Se) dietary Se. Gilts were bred and fetuses were collected throughout gestation. Concentrations of Se in maternal whole blood and liver decreased during gestation in sows fed the low-Se diet compared to sows fed the Se-supplemented diet. Maternal intake of Se did not affect the concentration of Se in the whole fetus; however, the concentration of Se in fetal liver was decreased in fetuses of sows fed the low-Se diet. Although fetal liver Se decreased in both treatments as gestation progressed, the decrease was greater in liver of fetuses from sows fed the low-Se diet. Dietary Se did not affect concentrations of Zn in maternal whole blood or liver or in the whole fetus and fetal liver. The concentration of Se in fetal liver was lower but the concentration of Zn was greater than in maternal liver when sows were fed the adequate Se diet. These results indicate that maternal intake of Se affects fetal liver Se and newborn piglets have lower liver Se concentrations compared to their dams, regardless of the Se intake of sows during gestation. Thus, the piglet is more susceptible Se deficiency than the sow.     

Cholesterol homeostasis in guinea pigs fed saturated and polyunsaturated fat diets

Whole body sterol balance, hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, hepatic low-density lipoprotein (LDL) receptor levels and net tissue cholesterol concentrations were determined in guinea pigs fed either a corn oil- or lard-based purified diet for 6-7 weeks. In comparison to the saturated lard diet, the polyunsaturated corn oil diet resulted in a 34% reduction in plasma total cholesterol levels (P less than 0.02) and a 40% lower triacylglycerol level (P less than 0.02). Feeding the corn oil diet altered very-low-density lipoprotein (VLDL) and LDL composition; the percent cholesterol ester in both particles was decreased and the relative percentages of VLDL triacylglycerol and LDL phospholipid increased. The ratio of surface to core components of LDL from corn oil-fed guinea pigs was significantly higher compared to LDL from animals fed lard. Dietary fat quality had no effect on fecal neutral or acidic steroid excretion, net tissue accumulation of cholesterol, whole body cholesterol synthesis or gallbladder bile composition. Consistent with these results was the finding that fat quality did not alter either expressed (non-phosphorylated) or total hepatic HMG-CoA reductase activities. The hepatic concentrations of free and esterified cholesterol were significantly increased in corn oil-fed animals, as were cholesterol concentrations in intestine, adipose tissue, muscle and total carcass. Analysis of receptor-mediated LDL binding to isolated hepatic membranes demonstrated that the polyunsaturated corn-oil based diet caused a 1.9-fold increase in receptor levels (P less than 0.02). The data indicate that the hypocholesterolemic effects of dietary polyunsaturated fat in the guinea pig are not attributable to changes in endogenous cholesterol synthesis or catabolism but rather may result from a redistribution of plasma cholesterol to body tissue due to an increase in tissue LDL receptors.     

Alteration of biliary ursodeoxycholic acid in guinea pig during early stages of cholestyramine feeding

The effects of cholestyramine feeding on biliary ursodeoxycholic acid, fecal excretion of bile acids and neutral sterols on cholesterol 7α-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 7α-hydroxylase activities. The fecal excretion of both bile acids and neutral sterols was significantly increased.     

Ontogeny of gluconeogenesis in the bovine fetus: influence of maternal dietary energy.

The influence of maternal energy intake on the development of gluconeogenesis was studied in the liver of the bovine fetus from Days 88 to 270 of gestation. Fetal liver activities (units per gram of tissue) of cytoplasmic GTP:oxalacetate carboxy-lyase (transphosphorylating) (PEPCK) and mitochondrial l-malate:NAD⁺ oxidoreductase (MDH) increased linearly with increasing gestational age. Fetal cytoplasmic MDH activities reached maternal levels by 120 days of gestation, and fetal mitochondrial pyruvate carboxylase approached maternal levels by 200 days of gestation. Fetal activities of mitochondrial and cytoplasmic propionyl-CoA:carbondioxide ligase (ADP-forming) (PCC) did not change with gestational age and were about 45 and 7%, respectively, of maternal levels. Fetal activities of mitochondrial and cytoplasmic l-aspartate: 2-oxoglutarate aminotransferase were both about 24% of the maternal activities throughout gestation. Maternal and fetal liver activities of d-fructose-1,6-diphosphate 1-phosphohydrolase (FDP) were similar and did not change with gestational age. Glucose synthesis from lactate by fetal liver slices in vitro was slightly lower and, from alanine and aspartate, was slightly higher than glucose synthesis by maternal liver slices. Restriction of maternal dietary energy intake did not significantly alter gluconeogenic-related enzyme activity in vitro in maternal or fetal liver or in the metabolism of aspartate, alanine, or lactate to glucose or CO₂ by liver slices in vitro. A capacity for gluconeogenesis has been measured in the bovine fetus as early as 88 days of gestation.     

Glutamine synthesis in the developing porcine placenta

Glutamine plays a vital role in fetal carbon and nitrogen metabolism and exhibits the highest fetal:maternal plasma ratio among all amino acids in pigs. Such disparate glutamine levels between mother and fetus suggest that glutamine may be actively synthesized and released into the fetal circulation by the porcine placenta. We hypothesized that branched-chain amino acid (BCAA) metabolism in the placenta plays an important role in placental glutamine synthesis. This hypothesis was tested by studying conceptuses from gilts on Days 20, 30, 35, 40, 45, 50, 60, 90, or 110 of gestation (n = 6 per day). Placental tissue was analyzed for amino acid concentrations, BCAA transport, BCAA degradation, and glutamine synthesis as well as the activities of related enzymes (including BCAA transaminase, branched-chain alpha-ketoacid dehydrogenase, glutamine synthetase, glutamate-pyruvate transaminase, and glutaminase). On all days of gestation, rates of BCAA transamination were much greater than rates of branched-chain alpha-ketoacid decarboxylation. The glutamate generated from BCAA transamination was primarily directed to glutamine synthesis and, to a much lesser extent, alanine production. Placental BCAA transport, BCAA transamination, glutamine synthesis, and activities of related enzymes increased markedly between Days 20 and 40 of gestation, as did glutamine in fetal allantoic fluid. Accordingly, placental BCAA levels decreased after Day 20 of gestation in association with a marked increase in BCAA catabolism and concentrations of glutamine. There was no detectable catabolism of glutamine in pig placenta throughout pregnancy, which would ensure maximum output of glutamine by this tissue. These novel results demonstrate glutamine synthesis from BCAAs in pig placentae, aid in explaining the abundance of glutamine in the fetus, and provide valuable insight into the dynamic role of the placenta in fetal metabolism and nutrition.     

Effects of mevinolin in rat liver: evidence for a lack of coupling between synthesis of hydroxymethylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase activity

The effect of treatment of rats with the hydroxymethylglutaryl-CoA reductase inhibitor, mevinolin, on 7 alpha-hydroxylation of cholesterol was studied. Treatment with 0.1% mevinolin in diet for 3 days was found to have an inhibitory effect on 7 alpha-hydroxylation of cholesterol (about 35%). Treatment with cholestyramine increased 7 alpha-hydroxylation of both exogenously added and endogenous microsomal cholesterol 3-4-fold. Combined treatment with both cholestyramine and mevinolin decreased this stimulation to 2-2.5-fold. Treatment with 2% cholesterol in diet increased 7 alpha-hydroxylation of exogenous cholesterol about 2-fold and 7 alpha-hydroxylation of endogenous cholesterol about 3.5-fold. The stimulatory effect of cholesterol was reduced or abolished when 0.1% mevinolin was added to the cholesterol-containing diet. With the exception of the experiments with cholesterol in the diet, all experiments including mevinolin gave a marked stimulation (up to 60-fold) of the hydroxymethylglutaryl-CoA reductase activity under the in vitro conditions employed. The concentration of free cholesterol in the liver microsomes was not significantly changed in any of these experiments. It is concluded that there is no coupling between induction of synthesis of hydroxymethylglutaryl-CoA reductase protein and cholesterol 7 alpha-hydroxylase activity. The inhibitory effect of mevinolin on cholesterol 7 alpha-hydroxylase activity under experimental conditions where most of the effect of mevinolin on hydroxymethylglutaryl-CoA reductase was abolished by treatment with cholesterol suggest that the effect of mevinolin on the cholesterol 7 alpha-hydroxylase may be independent of its effect on cholesterol synthesis. The over-all results do not favour the hypothesis that cholesterol synthesis and cholesterol availability are the most important determinants for the regulation of the cholesterol 7 alpha-hydroxylase.     

Effect of maternal diet on fetal hepatic lipogenesis.

The effects of: a, maternal diet; b, cyclic-3',5'-adenosinemonophosphate (cyclic AMP) and c, clofibrate on hepatic lipogenesis in fetal rats were studied. The experimental diets contained 22% protein, 40--50% carbohydrate, adequate vitamins, and minerals. In addition, the fat-containing diets were supplemented with either 15% corn oil, 25% corn oil, or 5% cholesterol + 10% oleic acid. In the clofibrate feeding studies, 0.3% (w/v) of the ethyl ester was added to a stock ration or to fat-free diet. Lipogenesis was measured in liver slices incubated with [2-14C]pyruvate, [1-14C]acetate, or 3H2O. In addition, activities of lipogenic enzymes were measured in cytosol fractions from liver homogenates. The effec-s of the experimental diets on liver composition were also examined. Lipogenic activity was higher in fetal than in maternal liver. When 15% corn oil was added to the maternal diet, fatty acid synthesis in fetal liver did not decrease as it did in maternal liver. Maternal fasting decreased fetal fatty acid synthesys by 50% when measured with 14C and less than 10% when measured with 3H2O. Although the addition of cholesterol to the maternal diet decreased cholesterol synthesis in maternal liver, no such decrease was observed in fetal liver. Changes in enzyme activities paralleled alterations in lipogenesis in maternal but not in fetal liver. Corn oil feeding or fasting increased the rate of transfer of linoleate from the dam to the fetus. However, accumulation of linoleate in fetal liver did not correlate with a decreased rate of fatty acid synthesis as it did in maternal liver. Maternal hepatic glycogen stores were depleted by fasting, but glycogen levels in fetal liver remained high under these conditions.     

Roles of nuclear receptors in the up-regulation of hepatic cholesterol 7alpha-hydroxylase by cholestyramine in rats

Nuclear receptors are involved in regulating the expression of cholesterol 7alpha-hydroxylase (CYP7A1), however, their roles in the up-regulation of CYP7A1 by cholestyramine (CSR) are still unclear. In the present study, male Wistar rats were divided into four groups and fed [high sucrose + 10% lard diet] (H), [H + 3% CSR diet] (H + CSR), [H + 0.5% cholesterol + 0.25% sodium cholate diet] (C), or [C + 3% CSR diet] (C + CSR) for 2 weeks. Cholestyramine decreased serum and liver cholesterol levels significantly in rats fed C-based diets, but had no effect on these parameters in rats fed H-based diets. Cholestyramine raised hepatic levels of CYP7A1 mRNA and activity in both groups. The gene expression of hepatic ATP-binding cassettes A1 and G5, regulated by liver X receptor (LXR), were unchanged and down-regulated by cholestyramine, respectively. The mRNA levels of the hepatic ATP-binding cassette B11 and short heterodimer partner (SHP), regulated by farnesoid X receptor (FXR), were not changed by cholestyramine. C-based diets, which contained cholesterol and cholic acid, increased SHP mRNA levels compared to H-based diets. Consequently, in rats fed the C+CSR diet, hepatic FXR was activated by dietary bile acids, but the hepatic CYP7A1 mRNA level was increased 16-fold compared to that in rats fed an H diet. These results suggest that cholestyramine up-regulates the expression of CYP7A1 independently via LXR- or FXR-mediated pathways in rats.     

The effect of maternal undernutrition on the growth and development of the guinea pig placenta.

Fetal growth is known to be correlated with the size of the placenta and the exchange surface area. Reduction in the growth of the materno-fetal exchange surface areas may be a mechanism by which the effects of maternal undernutrition on fetal growth are mediated. In the compact placenta of the guinea pig the exchange surface is equivalent to the peripheral labyrinth. The effect of a 40% reduction in maternal feed intake on the growth of the peripheral labyrinth was investigated in pregnant guinea pigs between gestational days 25 and 65. Fetal and placental weights were significantly reduced in the last trimester by 32% and 38% respectively (P < 0.01). Placental efficiency in early gestation was significantly impaired in restricted animals but equivalent to ad lib. fed controls by the last trimester. The volume of the peripheral labyrinth increased as a percentage of the total placental volume with gestational age. Restricted placentae tended to be composed of a smaller volume of peripheral labyrinth tissue in early gestation. It is suggested that maternal undernutrition results in an impaired or delayed expansion of the peripheral labyrinth in early gestation causing a reduction in placental efficiency. By the last trimester the weight of the peripheral labyrinth of restricted animals was reduced by 33% (P < 0.05). The weight of the peripheral labyrinth was also significantly correlated with fetal weight is limited by the size of the peripheral labyrinth in the later stages of gestation.     

Effect of dietary tomatine on cholesterol metabolism in the rat

Tomatine is a virtually nonabsorbable saponin which has been used as an antifungal agent and analytically as a cholesterol precipitant. It was used in this study to determine whether or not it can form a complex with cholesterol in vivo in the rat intestine and what effects such complex formation would have on cholesterol metabolism. Rats that were fed tomatine as 1% of the diet had a decreased uptake of dietary cholesterol by the liver, an increased rate of hepatic and intestinal cholesterol synthesis as well as a partial offsetting of the dietary cholesterol-induced decrease in hepatic cholesterogenesis, and an apparent increase in sterol excretion without an effect on bile acid excretion. In vitro, tomatine did not sequester cholic acid as did cholestyramine. The results show that tomatine has an effect on cholesterol absorption and on other aspects of lipid metabolism in the rat similar to that of cholestyramine, with the notable exception that tomatine increased sterol excretion while cholestyramine increased bile acid excretion. It was suggested that tomatine forms a nonabsorbable complex with cholesterol in the rat intestine.