Regulation of fecal bile acid excretion in male golden Syrian hamsters fed a cereal-based diet with and without added cholesterol

The objective of these studies was to investigate the comparative physiology and regulation of bile acid metabolism in the male Golden Syrian hamster by measuring the rate of fecal bile acid excretion and bile acid pool size in animals fed a cereal-based diet either alone, or with added cholesterol or cholestyramine. In group-housed hamsters fed only the plain diet fecal bile acid excretion in animals at 6, 10, and 15 weeks of age averaged 11.0, 8.0, and 6.9 mumol/d per 100 g body weight (bw), respectively. Pool size, measured by subtracting from the total amount of bile acid washed out over 12 hours of biliary diversion the amount of bile acid excreted in the stools over the same period, equalled 17.8 mumol/100 g bw in 15-week-old hamsters fed the plain diet. Hence, under basal conditions, these animals turned over about 38% of their bile acid pool daily. In hamsters fed a diet with 3% cholestyramine for 18 days, fecal bile acid excretion averaged 20.6 mumol/d per 100 g bw, and the pool size contracted to 5.8 mumol/100 g bw. In matching animals fed a diet containing 0.12% cholesterol for 30 days, hepatic cholesterol levels increased from 1.9 +/- 0.1 to 12.6 +/- 0.7 mg/g, fecal bile acid excretion increased marginally from 5.8 to 8.0 mumol/day per 100 g bw, while pool size was unchanged (16.6 mumol/100 g bw). When the cholesterol content of the diet was raised to 1.0%, hepatic cholesterol levels reached 66.5 +/- 2.6 mg/g, but bile acid excretion remained at 8 mumol/d per 100 g bw. These data define some of the basal features of bile acid metabolism in the hamster, and substantiate the view that the marked cholesterolemic response of this species may relate partly to a limited ability to convert dietary cholesterol to bile acid.     

Effect of felodipine on arterial blood flow and venous function at rest in patients with mild essential hypertension

OBJECTIVES: Lipid-lowering drugs as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors and cholestyramine are effective in reducing cardiovascular morbidity both in primary and secondary prevention. Patient compliance is an important determinant of the outcome of therapy. This study was designed to compare compliance with tolerance and lipid-lowering effectiveness of pravastatin and/or cholestyramine in primary care. DESIGN: Nine hundred and eighty nine women and 1047 men were randomized to treatment at 100 primary-care centres in Sweden. After dietary intervention, an eligible patient was randomly assigned to one of four programs of daily treatment: group Q, 16 g cholestyramine, group QP, 8 g cholestyramine and 20 mg pravastatin, group P20, 20 mg pravastatin or group P40, 40 mg pravastatin. RESULTS: In group Q, group QP, group P20 and group P40 the reductions in low density lipoprotein (LDL)-cholesterol were 26%, 36%, 27% and 32%. The dose actually taken was 91-95% of the prescribed for the pravastatin treatment groups and 77-88% for the cholestyramine groups. In the pravastatin and cholestyramine groups 76-78% and 44-53%, respectively, completed the trial. Only 8-27% of the patients reached a serum cholesterol target level of 5.2 mmol L-1. There was no difference in lipid-lowering effect between women and men. CONCLUSION: Pravastatin alone is efficacious and compliance is high, independent of dose. Combined treatment with cholestyramine and pravastatin had a better cholesterol lowering effect (although not statistically significant) than 40 mg pravastatin. Despite this, only 8-27% of the patients actually reached a serum cholesterol level of 5.2 mmol L-1. No unexpected serious adverse events were detected in any of the treatment groups. As predicted, the gastrointestinal disturbances were more common on cholestyramine treatment. These two factors suggest that an increase in the dosage of the HMG-CoA reductase inhibitor may be appropriate. Results from other studies indicate that there also might be other positive effects of statin treatment beyond cholesterol lowering.     

Effect of cholesterol and cholestyramine feeding and of fasting on sterol synthesis in the liver, lleum, and lung of the guinea pig

The effects of feeding diest containing either cholesterol (0.24% w/w) or cholestyramine (2.5% w/w) and of fasting on sterol synthesis in the liver, ileum, and lung of both male and female guinea pigs have been studied by measuring the incorporation by tissue slices of 14C-labeled acetate into total digitoninpredipitable sterols. Cholesterol feeding significantly decreased (P less than 0.05) sterol synthesis in the liver, ileum, and lung of the males and in the ileum of females. Cholestyramine feeding stimulated the rate of hepatic sterol synthesis 13-fold but did not significantly affect sterologenesis in the ileum. Sterol synthesis in the lung was significantly increased (P less than 0.05) but to a much lesser extent than in the liver. Fatty acid synthesis in the liver, ileum, and lung was not significantly affected by either cholesterol or cholestyramine feeding. In guinea pigs fasted for 24 hr, sterol synthesis was inhibited in all three tissues, the most pronounced effect occurring in the liver. Only in the lung was fatty acid synthesis significantly decreased (P less than 0.001) by fasting. Cholesterol feeding resulted in increased concentrations of cholesterol in the plasma and liver. Cholestyramine feeding reduced plasma cholesterol concentration by 81% in females and by 64% in males. However, it did not significantly change the tissue cholesterol concentrations. Fasting resulted in a significant increase (P less than 0.05) in plasma cholesterol concentration but did not effect the concentration of cholesterol in the tissues. It was concluded that in the normal guinea pig, the feedback inhibition produced by both cholesterol and also possibly by bile acids suppresses sterol synthesis in the liver to very low rates compared to those in the small intestine, where sterologenesis is not only less sensitive to the cholesterol negative feedback system than that in the liver, but also is not subject to regulation by the bile acid negative feedback system.     

Absorption, metabolism, and serum concentrations of cholesterol in vegetarians: effects of cholesterol feeding

Serum concentrations and metabolism of cholesterol were studied in vegetarians basally and during a dietary cholesterol load. Cholesterol absorption efficiency was normal and synthesis was slightly enhanced, even though serum cholesterol precursors were not increased. The serum concentrations of total and low-density-lipoprotein cholesterol were decreased proportionally to the reduced intake and absolute absorption of cholesterol. Fecal plant sterols were negatively correlated with the absorption efficiency of cholesterol and positively with fecal sterols and cholesterol synthesis, suggesting interference of high plant sterol intakes with cholesterol absorption. Cholesterol saturation and bile acid composition of the bile were not changed. The increased serum plant sterol-cholesterol ratios were positively related to the intake and negatively to the biliary secretion of plant sterols. Cholesterol feeding increased absolute cholesterol absorption and serum concentrations of total and low-density-lipoprotein cholesterol, did not change absorption efficiency or synthesis of cholesterol, but increased fecal cholestanol excretion.     

Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia

In familial hypercholesterolemia (FH) the lowering of serum cholesterol levels should be started in childhood in order to prevent coronary artery disease later in life. However, treatment of children is problematic. We studied the effects of sitostanol (3 g/day) ester dissolved in rapeseed oil margarine as a hypocholesterolemic agent in one homozygous and 14 heterozygous children with FH maintained on a low cholesterol diet for 6 weeks, using a double-blind crossover design. Absorption and synthesis of cholesterol were evaluated by measuring serum plant sterol and cholesterol precursor proportions to cholesterol by gas-liquid chromatography. The compliance was good, and the children could not distinguish by taste the two margarines without and with sitostanol ester. Sitostanol margarine significantly reduced serum total, intermediate density (IDL), and low density lipoprotein (LDL) cholesterol by 11, 26, and 15%, respectively, and increased HDL/LDL cholesterol ratio by 27%. The proportions of serum delta 8-cholestenol, lathosterol, and desmosterol were significantly increased by 36, 19, and 18%, and those of serum cholestanol, campesterol, and sitosterol were significantly decreased by 9, 42 and 29%, respectively, suggesting that cholesterol absorption was decreased and synthesis was compensatorily increased. High basal precursor sterol proportions predicted a high decrease in LDL cholesterol levels. In conclusion, partial replacement of normal dietary fat consumption by sitostanol ester margarine appears to be an effective and safe hypocholesterolemic treatment in children with FH.     

Effect of pectin on serum cholesterol, fecal bile acids and biliary lipids in normolipidemic and hyperlipidemic individuals

Pectin, 40-50 g/day for two weeks administered to nine normolipidemic and hyperlipidemic patients, had no effect on serum triglycerides but did cause a significant decrease in the serum total and unesterified cholesterol of hypercholesterolemic subjects in particular. This was associated with increased excretion of fecal bile acids and total steroids and increased concentration of plasma methyl sterols. Thus, the serum cholesterol reduction by pectin appears to be caused by increased cholesterol elimination into stools as bile acids which is then balanced by enhanced cholesterol synthesis. The composition of biliary bile acids and lipids was not changed and secondary bile acids and sterols decreased inconsistently in feces. The measurement of fecal dry weight suggested that the bulk of the pectin was degraded by bacteria during passage through the intestine. Consequently fecal mass and dry weight were not consistently increased, suggesting that pectin may not be an ideal fibre for increasing fecal bulk in functional colonic disorders.     

Cholesterol absorption in man: effect of administration of clofibrate and/or cholestyramine

Cholesterol absorption measurements were carried out in a free-living out-patient population by a plasma isotope-ratio method previously validated for in-patients (Samuel, P., J. R. Crouse and E. H. Ahrens, Jr., 1978. J. Lipid Res. 19: 82-93). To test the reproducibility of the method in out-patients, 18 patients were tested twice: the mean intra-assay variability was +/- 6.0%. The method was then applied in 150 hyperlipidemic male out-patients, ingesting a standardized diet containing 250mg cholesterol per day, who had been randomized into four different drug-treatment groups: 1) no medication, 2) clofibrate, (2g/day), 3) cholestyramine (16g/day), or 4) both clofibrate and cholestyramine. Cholesterol absorption (as percent of the oral dose) was increased in patients receiving cholestyramine (P < 0.02) and decreased in those receiving clofibrate (P < 0.02); the group on the combined medication had the same pecent absorption as the control group. In twelve patients receiving cholestyramine, a second test of cholesterol absorption was performed 30 min after each patient had received 8g of cholestyramine. The pre-test administration of cholestyramine caused a 38% decrease in cholesterol absorption (P < 0.001), compared to results obtained when medication was withheld prior to testing. These results demonstrate that the isotope-ratio method of measuring cholesterol absorption is a reproducible procedure applicable to a free-living out-patient population, and that the hypolipidemic drugs, clofibrate and cholestyramine, significantly affect cholesterol absorption in man. The data also show that the results of measurements of cholesterol absorption can be profoundly altered by the type and timing of medication in relationship to the test meal of labeled cholesterol.     

Breast cancer imaging--what are the optimal modalities?

Different soluble dietary fibers known to alter cholesterol metabolism were fed to golden Syrian hamsters, and their specific impact on lipoproteins, biliary bile acid profile, and fecal sterol excretion was evaluated. Semipurified diets containing 20% fat; 0.12% cholesterol; and 8% of psyllium (PSY); high (hePE) and low (lePE) esterified pectin; or high (hvGG) and low (lvGG) viscous guar gum were fed for 5 wk. Compared to control, PSY caused a significant reduction in plasma cholesterol (2.9 +/- 0.5 vs. 5.5 +/- 0.5 mmol/L), whereas hePE, lePE, hvGG, or lvGG had no apparent effect on plasma lipids. Hepatic total and esterified cholesterol were substantially decreased with PSY, pectin and guar gum, whereby PSY produced the most pronounced effect. Distinctive changes existed in the bile acid profile related to the different fibers. In contrast to pectin and guar gum, PSY caused a significant increase in the cholate:chenodeoxycholate and the glycine:taurine conjugation ratio. Pectin and guar gum did not alter daily fecal neutral sterol excretion while PSY caused a 90% increase due to a higher fecal output. Daily fecal bile acid excretion and total fecal bile acid concentration were significantly increased by PSY, whereas hePE, lePE, hvGG, and lvGG revealed no or only minor effects. Taken together, the disparate hypocholesterolemic effects of PSY, pectin, and guar gum on cholesterol and bile acid metabolism in the hamster are possibly related to different physicochemical properties, e.g., viscosity and susceptibility to fermentation, affecting the fiber-mediated action in the intestine.     

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any gender-related differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 micromol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 micromol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25. 3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2. 1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 micromol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels.     

Hypocholesterolemic action of a novel delta8-dihydroabietamide derivative, THD-341, in rats

The hypocholesterolemic properties of THD-341, N-(2,6-dimethylphenyl)-delta8-dihydroabietamide, were studied in rats. THD-341 reduced serum cholesterol levels in cholesterol-cholate-fed rats at a concentration of less than 0.001% in the diet or an oral dose of less than 3 mg/kg, once a day. When compared in terms of the 50% inhibitory dose for serum cholesterol elevation (ID 50%, % in diet), THD-341 (0.0008%) was comparable to D-thyroxine (0.0005%), more potent than estradiol (0.003%), and far more potent than clofibrate (0.2%), beta-sitosterol (0.8%), cholestyramine (2%), or nicotinic acid (3%). A daily intravenous injection of THD-341 was also effective (ID 50%: 7 mg/kg). THD-341 reduced serum and liver cholesterol in rats made hypercholesterolemic by 0.3% dietary thiouracil or 0.25% dietary cholate. Liver cholesteriol was more profoundly affected than the serum cholesterol. In normal rats, cholesterol was reduced in liver but not in serum. Its mechanism of action is unknown but the results suggest that THD-341 inhibits cholesterol absorption or re-absorption.     

Dietary inulin lowers plasma cholesterol and triacylglycerol and alters biliary bile acid profile in hamsters

The mechanisms by which inulin may elicit its lipid-lowering effect are not well elucidated. To examine the lipid-lowering potential of inulin and especially its effect on bile acid metabolism, male golden Syrian hamsters were fed semipurified diets containing 20 g/100 g fat, 0.12 g/100 g cholesterol and 0 (control), 8, 12 or 16% inulin for 5 wk. Plasma total cholesterol concentrations were significantly lowered by 18, 15 and 29% in hamsters fed 8, 12 and 16% inulin, respectively. Dietary inulin specifically decreased VLDL cholesterol, which was significantly lower in hamsters fed 16% inulin compared with controls (1.1 +/- 0.3 vs. 2.9 +/- 0.6 mmol/L). LDL and HDL cholesterol were not significantly affected by dietary inulin. Plasma triacylglycerol was significantly reduced by 40 and 63% in hamsters fed 12 and 16% inulin, respectively. Hepatic total cholesterol and particularly esterified cholesterol accumulation were significantly lower in hamsters fed 8% inulin compared with controls. All three levels of dietary inulin caused distinct alterations in the bile acid profile of gallbladder bile. Taurochenodeoxycholic acid was significantly lower, whereas glycocholic and glycodeoxycholic acid were greater in hamsters fed inulin. Daily fecal bile acid excretion (micromol/d) tended to be greater (P = 0.056) in inulin-fed hamsters compared with controls, whereas daily neutral sterol excretion was not affected. These data demonstrate that the lipid-lowering action of inulin is possibly due to several mechanisms, including altered hepatic triacylglycerol synthesis and VLDL secretion and impaired reabsorption of circulating bile acids.     

The effects of simvastatin and cholestyramine, alone and in combination, on hepatic cholesterol metabolism in the male rat. off

The influence of dietary simvastatin, cholestyramine, and the combination of simvastatin plus cholestyramine on hepatic cholesterol metabolism has been investigated in male rats. Recovery from the effects of the drugs was also investigated by refeeding normal chow for 24 h. Both drugs, alone and in combination, increased 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in vitro, but activity returned toward control values, after drug withdrawal. Acyl-CoA:cholesterol acyltransferase (ACAT) was significantly reduced (P < 0.001) by simvastain (-75%), cholestyramine (-71%), and by the drug combination (-81%), due both to a decrease in microsomal cholesterol and to nonsubstrate-dependent modulation of enzyme activity. Refeeding control diet increased ACAT activity but not to control levels. The enhanced activity arose partly from higher microsomal cholesterol and partly from increases in total enzyme activity. Cytosolic neutral cholesteryl ester hydrolase (CEH) activity was substantially elevated by simvastatin (3-fold) and by the drug combination (6-fold), whereas the effect of cholestyramine was smaller (1.5-fold). Normal chow for 24 h only partially returned cytosolic CEH activity to control values. Microsomal CEH activity was increased by simvastatin, alone and in combination with cholestyramine (1.4 to 1.7-fold), and was also enhanced, in the cholestyramine-treated animals, following drug withdrawal. Removal of simvastatin did not allow recovery of this enzyme activity, while withdrawal of the drug combination led to values 29% below controls. The results indicate that in the rat, simvastatin and cholestyramine alter both ACAT and CEH activity, as well as inhibiting HMG-CoA reductase activity.     

von Willebrand''s disease and plastic surgery

Von Willebrand's disease (VWD) is the most commonly inherited coagulopathy. In a group of 1,000 plastic surgery patients, 8 or 9 individuals are affected by this disease, making basic knowledge of VWD and its management imperative. In this investigation, 1,000 plastic surgery patients were studied for details of their clinical evaluation, history of bleeding and bruising, and excessive bleeding during or after surgery. If the patient reported a history of easy bleeding or bruising, in addition to routine coagulation studies such as PT, PTT, and platelet count, the bleeding time was measured. When the index of suspicion dictated, more extensive coagulation studies, such as factor VIII assay, were conducted. This resulted in the detection of VWD in 9 patients (8 female and 1 male). All patients had a positive history of easy bleeding or bruising. Six of the 9 patients had a bleeding time greater than 6 minutes. Seven patients were diagnosed to have VWD type I, 1 had type II-a, and 1 suffered from type II-b disease. Perioperative bleeding was controlled in all patients in this study with the administration of 0.3 microgram/kg of body weight (usually a total dose of 20 micrograms) of 1-deamino-8-D-arginine-vasopressin intravenously every 12 hours for the first 24 hours. Two patients with type II VWD required fresh frozen plasma and cryoprecipitate 1 week subsequent to surgery to control late bleeding.     

Plasma and hepatic cholesterol levels and fecal neutral sterol excretion are altered in hamsters fed straw mushroom diets

The effect of the fruiting body and mycelium of Volvariella volvacea (straw mushroom) on the concentrations of plasma lipids, liver cholesterol, fecal neutral sterol and bile acid excretions was investigated in male Golden Syrian hamsters. The hamsters were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 4 wk to elevate plasma lipid concentrations. Twelve hamsters with elevated plasma total cholesterol were randomly assigned to each treatment group: control (5% cellulose), mushroom fruiting body (5%) and mushroom mycelium (5%). After 4 wk of mushroom diet consumption, the plasma total cholesterol, HDL cholesterol, and combined VLDL + LDL cholesterol concentrations (mmol/L) were significantly lower than control in the group fed the fruiting body-diet (40, 38 and 43%, respectively) (P < 0.05). The liver cholesterol levels were significantly lower in both the mushroom fruiting body- and the mycelium-fed groups (28 and 21% in terms of concentration; 39 and 30% in terms of total content, respectively) (P < 0.05) than that in the control group. Fecal neutral sterol excretion in the mushroom fruiting body- and mycelium-fed groups was significantly higher (81 and 74%, respectively) (P < 0.05) than that in the control group. Although no significant differences (P > 0.05) in the excretion of fecal bile acids were observed among groups fed the mushroom diets and the control diet, the mushroom fruiting body diet-fed hamsters apparently had less bacterial degradation of cholic acid as indicated by a significantly greater proportion (P < 0.05) of fecal cholic acid than in controls. They also had a significantly lower proportion of fecal deoxycholic acid (P < 0.05). This study suggests that the fruiting body of the straw mushroom lowers elevated plasma cholesterol in hypercholesterolemic hamsters, whereas the mycelium does not.     

Ionization constants and distribution coefficients of phenothiazines and calcium channel antagonists determined by a pH-metric method and correlation with calculated partition coefficients

We investigated the effect of increasing dietary cholesterol on bile acid pool sizes and the regulation of the two bile acid synthetic pathways (classic, via cholesterol 7alpha-hydroxylase, and alternative, via sterol 27-hydroxylase) in New Zealand white rabbits fed 3 g cholesterol/per day for up to 15 days. Feeding cholesterol for one day increased hepatic cholesterol 75% and cholesterol 7alpha-hydroxylase activity 1.6 times without significant change of bile acid pool size or sterol 27-hydroxylase activity. After three days of cholesterol feeding, the bile acid pool size increased 83% (P < 0.01), and further feeding produced 10%-20% increments, whereas cholesterol 7alpha-hydroxylase activity declined progressively to 60% below baseline. In contrast, sterol 27-hydroxylase activity rose 58% after three days of cholesterol feeding and remained elevated with continued intake. Bile drainage depleted the bile acid pool and stimulated downregulated cholesterol 7alpha-hydroxylase activity but did not affect sterol 27-hydroxylase activity. Thus, increasing hepatic cholesterol does not directly inhibit cholesterol 7alpha-hydroxylase and initially favors enzyme induction, whereas increased bile acid pool is the most powerful inhibitor of cholesterol 7alpha-hydroxylase. Sterol 27-hydroxylase is insensitive to the bile acid flux but is upregulated by increasing hepatic cholesterol.     

Phytosterolaemia in three unrelated South African families

Phytosterolaemia (beta-sitosterolaemia), a rare, autosomal recessive disorder, has not hitherto been reported in Southern Africa. We report four new homozygous patients, from three unrelated families with significant beta-sitosterolaemia (6.6-11.3%), campesterolaemia (2.2-4.6%) and clearly detectable, though unquantified, levels of cholestanol. Three of the four patients had characteristic cutaneous and tendinous xanthomas within the first decade of life. The fourth patient, a 5 year old, was free of xanthomas despite persistently elevated concentrations of plant sterols in her plasma. All our patients were female bringing the male:female ratio in reported cases to 8:23. All were at or below the 50th percentile for height and weight, and presented at some stage with borderline, hypochromic anaemia associated with red cell abnormalities and thrombocytopaenia. The oldest patient showed suggestive clinical evidence of atherosclerosis affecting her aorta, ileofemoral bifurcation and possibly coronary arteries. All homozygotes responded to a diet restricted in phytosterols and the administration of cholestyramine with falls in plasma sterols of up to 68%. The recent discovery of a possible inherited defect in the synthesis of HMG CoA reductase in patients with phytosterolaemia makes this disorder a model system for studying the biological role of this enzyme in regulating the absorption and clearance of sterols other than cholesterol, and the factors governing the sterol composition of cell membranes.     

The effects of various diphosphonates on a rat model of cardiac calciphylaxis

Compartmental analysis of the disappearance curve of serum cholesterol specific activity after an intravenous administration of a tracer does of cholesterol-4-14C was carried out in five patients with resection of the distal small intestine, cecum, and proximal colon. The data fit best a two compartment model in all five cases with the rapidly exchangeable pool of 16.6+/-3.2 g (mean +/- SD, 60% of the mean of 15 normal subjects) and the slowly exchangeable pool of 31.5 +/- 10.9 g (65%). The reduction of the pool sizes was associated with a shorter mean transit time of cholesterol, 22.15 +/- 8.07 days (40%) and increased turnover rate, 2.42 +/- 0.72g/ day (172%). Direct fecal analysis for the neutral sterols and bile acids derived from the exchangeable pool confirmed the turnover rate obtained from the compartmental analysis. The increased fecal excretion was mainly in the bile acid fraction. The study suggests that the ileal and proximal colon resection results in bile acid malabsorption which, in turn, increases hepatic cholesterol and bile acid synthesis. The synthetic rates, however, could not compensate totally for the excretory rate. Therefore, the pool size decreased to a new low steady state of equilibrium.     

Cholestyramine and a fat-free diet lower apolipoprotein A-IV mRNA in jejunum and cholestyramine lowers apolipoprotein A-I mRNA in ileum of rats

To investigate the effect of bile acids or dietary lipid on the expression of intestinal apolipoproteins, the mRNA levels of apolipoprotein A-I and A-IV in the intestine from rats fed a diet containing cholestyramine or a fat-free diet were compared with those from rats fed a control diet containing 25% casein and 5% corn oil. Plasma total cholesterol concentration was lower after 16 h in rats fed a diet containing cholestyramine or a fat-free diet than in rats fed a control diet. In rats fed the fat-free diet, HDL cholesterol concentration also was lower than in those fed the control diet. The pool of bile acid in intestinal contents was significantly lower in rats fed cholestyramine than in both other groups. The relative abundance of jejunal apolipoprotein A-I mRNA did not differ between groups. Jejunal apolipoprotein A-IV mRNA abundance was significantly lower than in controls in rats fed the fat-free and cholestyramine-containing diets. Abundance of apolipoprotein A-I mRNA in ileal mucosa was comparable to controls in rats fed a fat-free diet but was significantly lower in rats fed cholestyramine. Ileal apolipoprotein A-IV mRNA tended to be lower in rats fed cholestyramine and a fat-free diet than in controls. We propose that decreased absorption of dietary lipid may modulate changes in jejunal apolipoprotein A-IV mRNA level and low levels of bile acids in the lumen may modulate changes in ileal apolipoprotein A-I mRNA level.     

Fecal bile acids and neutral sterols in patients with familial polyposis

Fecal neutral steroids and bile acids were measured in patients with familial polyposis, family controls who are immediate relatives of patients, and controls other than relatives. All subjects were consuming a mixed Western diet at the time of collection of stool specimens. Although the total fecal neutral sterol concentrations were not different between the groups, the patients with familial polyposis excreted a high amount of cholesterol and low levels of coprostanol and coprostanone compared with other groups. Patients with familial polyposis excreted levels of total bile acids in their feces comparable to those excreted by controls; lithocholic acid excretion was decreased in patients with familial polyposis. These findings suggest that analysis of stools for cholesterol and its metabolites be useful in screening the siblings of polyposis families for latent disease.     

Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene

Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7alpha-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.