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.     

Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway

Reduced cholesterol synthesis has been reported in patients with primary biliary cirrhosis but no data are available on changes in cholesterol catabolism induced by the disease. Serum levels of 7alpha-hydroxycholesterol and 27-hydroxycholesterol have been measured in 25 patients (either normocholesterolemic or hypercholesterolemic) with primary biliary cirrhosis and in control subjects. To evaluate cholesterol synthesis, serum levels of lathosterol were measured, and campesterol and sitosterol were considered to reflect intestinal absorption and biliary elimination of sterols. In normocholesterolemic patients with primary biliary cirrhosis, lathosterol was significantly lower than in normocholesterolemic controls (P < 0.05) whereas no difference was found between hypercholesterolemic patients and hypercholesterolemic controls. Serum concentrations of sitosterol were significantly higher in both normocholesterolemic and hypercholesterolemic patients with primary biliary cirrhosis as compared with the respective controls (P < 0.01). In patients with primary biliary cirrhosis, serum 7alpha-hydroxycholesterol was slightly higher than in controls. 27-Hydroxycholesterol was significantly higher in hypercholesterolemic compared to normocholesterolemic controls (P < 0.05) and a significant linear correlation (r = 0.771; P < 0.001) was found between 27-hydroxycholesterol and cholesterol. In contrast, in patients with primary biliary cirrhosis, high cholesterol concentrations were not associated with increased serum levels of 27-hydroxycholesterol. Our data confirm that in patients with primary biliary cirrhosis, cholesterol synthesis and biliary elimination of sterols are impaired and also suggest that both the feedback regulation of retained bile acids on cholesterol 7alpha-hydroxylase and the scavenger effect on elevated serum cholesterol by cholesterol 27-hydroxylase are deficient in these patients. acids via the acidic pathway.     

Composition of biliary lipids and kinetics of bile acids after cholecystectomy in man

Postcholecystectomy biliary lipid composition and bile acid kinetics were studied in 24 women and 4 men. Hepatic bile was collected periodically for as long as 4 months without interrupting the enterohepatic circulation and without infecting the biliary system. In 23 patients with cholesterol gallstones, fasting biliary cholesterol made up 10.2% of total lipids in the steady state; in 5 patients with bilirubinate stones, saturation of fasting hepatic bile with cholesterol was lower (8.7% of total lipids). The percentage of deoxycholic acid after cholecystectomy was not higher than that of seven healthy, noncholecystectomized controls. Postcholecystectomy studies of diurnal variation of biliary lipids (7 patients) showed that postprandial hepatic bile had a significantly lower cholesterol saturation than fasting bile. Pool sizes of cholic and chenodeoxycholic acids were low (average 0.4 g/70 kg, each); total synthesis for both bile acids was normal (average 460 mg/day/70 kg), but fractional turnover rates of the two primary bile acids increased after cholecystectomy, probably due to more frequent recycling of the small bile acid pool.     

Changes in phenotypic expression of osteoblasts after X irradiation

The effect of high- (hePE) and low- (lePE) esterification pectin and high- (hvGG) and low-(lvGG) viscosity guar gum on plasma, hepatic and biliary lipids and on prevention of cholesterol gallstones was investigated in male golden Syrian hamsters (Mesocricetus auratus). Hamsters were fed on cholesterol-rich (4 g/kg), gallstone-inducing diets for 6 weeks. The diets were supplemented with 80 g hePE, lePE, hvGG or lvGG/kg or 80 g additional cellulose/kg. No significant differences in plasma total cholesterol and triacylglycerol concentrations between hvGG and lvGG and the gallstone-inducing or cellulose-enriched diets were observed. The hePE diet produced a 16% (non-significant) reduction in total plasma cholesterol but significantly decreased the plasma triacylglycerol level by 45%. The lePE diet caused only minor changes in plasma lipids. Hepatic cholesterol concentrations were significantly higher in hamsters fed on hvGG, lvGG, hePE or lePE primarily due to the accumulation of esterified cholesterol. Supersaturated bile samples, with lithogenic indices ranging from 1.6 to 2.0, were determined with all diets. The hePE and lePE diets slightly altered the bile acid profile by increasing glycocholic acid and decreasing taurochenodeoxycholic acid concentrations resulting in a higher cholic:chenodeoxycholic acid ratio. Cholesterol gallstone formation was not substantially inhibited by the two varieties of pectin and guar gum. The hvGG, lvGG, hePE and lePE diets did not alter faecal weight and caused only minor increases in faecal bile acid excretion. In general, the present findings demonstrate that dietary pectins and guar gums had only minor effects on cholesterol metabolism and did not prevent cholesterol gallstone formation in this hamster model. Possible explanations for this lack of a distinct response to pectin and guar gum are discussed.     

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 and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoE phenotypes

The aim of the present study was, first, to investigate whether cholesterol (C) absorption, enhanced by cholesterol feeding, was related to synthesis of cholesterol, serum level of low density lipoprotein (LDL)-C, and receptor activity for LDL apolipoprotein (apo) B in healthy men. Secondly, we were interested in whether apolipoprotein E (apoE) phenotypes contributed to cholesterol and LDL apoB metabolism under these conditions. We studied 29 home-living men aged 55 +/- 1 (mean +/- SE) years on a low-fat, low cholesterol (208 +/- 13 mg/day) diet followed by a low-fat high cholesterol (878 +/- 38 mg/day) diet during 5 weeks. Cholesterol feeding increased total cholesterol, LDL-C, high density lipoprotein (HDL)-C, and LDL apoB levels from 10% to 13% (P less than 0.05) and bile acid production and cholesterol turnover by 16% (P less than 0.05), decreased the fractional catabolic rate (FCR) for LDL apoB by 10% (P less than 0.05) and cholesterol absorption efficiency by 8% (P less than 0.05), while cholesterol synthesis only tended to decrease. During the cholesterol feeding, LDL-C was positively related to apoB production rate and cholesterol absorption efficiency (P less than 0.05), and negatively related to bile acid and cholesterol synthesis (P less than 0.05) and FCR for LDL apoB, which, in turn, was negatively related to cholesterol absorption efficiency and positively to bile acid synthesis. ApoE phenotype was positively related to TC, LDL-C, and LDL apoB levels and negatively to FCR for LDL apoB. The increase of the LDL-C level by the high cholesterol intake was positively correlated with LDL-C on high cholesterol diet and apoE phenotypes, so that the increase was 7% in apoE2 (ns), 11% in apoE3 (P less than 0.05), and 18% in apoE4 (P less than 0.05); the increase of bile acid synthesis was significant only in subjects with apoE2. Moreover, the increase of LDL-C was positively related to the absolute amount of dietary cholesterol absorbed and negatively to FCR for LDL apoB. The findings suggest that the higher the LDL-C level, the higher is the absorption efficiency of cholesterol and production of LDL apoB, and the lower is the removal of LDL apoB and synthesis of both bile acids and cholesterol, and the more frequently the subjects had epsilon 4 allele. The nonresponsiveness to dietary cholesterol was dependent on low LDL-C level, apoE2 phenotype, and effective bile acid synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of cholesterol absorption in rats using markers labeled with stable isotopes. Effect of complete bile diversion

BACKGROUND/AIMS: An easily performed method to measure cholesterol absorption with isotope labeled cholesterol and beta-sitostanol in humans is described. The first aim of the study was to show whether this method can also be used in rats. Secondly, to see whether complete bile diversion results in a complete loss of cholesterol absorption. METHODOLOGY: Cholesterol absorption was evaluated in rats by the constant isotope feeding method using [2H6]cholesterol and [2H4]sitostanol as markers. Fecal samples were analyzed by gas-chromatography/mass spectrometry. RESULTS: In 8 rats with intact enterohepatic circulation of bile acids, cholesterol absorption averaged 61 (3% (SD) (range: 54-69%)). Complete bile diversion was followed by an almost total loss of cholesterol absorption (5.5+/-0.6%, range: 2.4-6.9%, n=7). CONCLUSIONS: The results indicate that deuterated cholesterol and deuterated sitostanol are reliable markers for measurement of cholesterol absorption in rats and that bile acids are essential for cholesterol absorption.     

Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the rat

BACKGROUND & AIMS: Cholesterol degradation to bile acids occurs via "classic" or "alternative" bile acid biosynthetic pathways. The aim of this study was to assess the contributions of these two pathways to total bile acid synthesis in vivo. METHODS: Rats with biliary fistulas were infused with squalestatin for 24 and 48 hours; specific activities of cholesterol 7 alpha-hydroxylase (C7 alpha H) and sterol 27-hydroxylase (S27H) and rates of bile acid synthesis were determined. RESULTS: Continuous squalestatin infusion (15 micrograms/h) decreased C7 alpha H specific activities to 4% and 12% of paired biliary fistula controls at 24 and 48 hours, respectively (P < 0.05) without any changes in S27H specific activities (82% and 95% of controls). At 24 hours, bile acid synthesis decreased to 43% (P < 0.05) but returned to 87% at 48 hours (P = NS). Cholic acid synthesis decreased at 24 hours but returned to control levels at 48 hours. Similar changes in C7 alpha H, S27H, and bile acid synthesis were observed in primary rat hepatocytes after addition of squalestatin (1.0 mumol/L). CONCLUSIONS: In the face of persistent suppression of C7 alpha H and the classic pathway, an alternative pathway becomes a main pathway of bile acid synthesis capable of generating cholic and chenodeoxycholic acids. The observed induction of bile acid synthesis via an alternative pathway or pathways represents an important mechanism for maintenance of cholesterol homeostasis in the rat.     

Does lipid infusion affect bile composition in humans?

A prospective study was performed to investigate the effect of short-term lipid infusion on bile composition and its lithogenicity in humans. The study group comprised 44 patients scheduled for laparotomy. The patients were hospitalized 48 h prior to elective surgery and randomized to be infused with a lipid emulsion of either long chain triglycerides (LCT) or a mixture of medium and long chain triglycerides (MCT/LCT) for 6 h of each 24 h, or with glucose-saline. Bile samples were obtained by puncture of the gallbladder during operation. In non-gallstone patients, both lipids caused an elevation of biliary cholesterol and phospholipids, but this effect was more pronounced and significant (P <0.001) only with the mixture of MCT/LCT emulsion. The fatty acid composition of biliary phospholipids was not affected by either lipid infusion. The Cholesterol Saturation Index increased significantly (P <0.005) with the MCT/LCT emulsion and there was insignificant shortening in the nucleation time. In contrast to patients with cholelithiasis, no effects could be demonstrated on gallbladder bile composition, cholesterol saturation index, nucleation time, or fatty acid composition of phospholipids. The effects of both lipid emulsions on plasma lipids and lipoproteins were similar in all groups. Our results indicate that lipid emulsions containing MCT/LCT induce lithogenic changes in the composition of human bile. We propose that the lack of effect of lipid infusion on bile composition in patients with cholelithiasis may be due to precipitation of excess cholesterol in the gallbladder of cholesterol gallstone patients whose bile is already saturated. These findings imply that patients with cholesterol gallstones cannot be grouped with non-gallstone patients in studies of alterations of bile composition.     

Thyroid hormone is required for dietary fish oil to induce hypersecretion of biliary cholesterol in the rat

In the rat, both fish oil diet and thyroid hormone replacement are reported to augment bile cholesterol secretion out of proportion to bile flow or secretion of other bile lipids. We sought common mechanisms for these effects and evaluated the role of phospholipid fatty acid composition in the process. Methimazole-treated hypothyroid rats were fed low-fat chow or chow supplemented with 10% corn oil or fish oil, and were studied before and after thyroid hormone treatment. Serum, hepatic, and bile lipids were measured, phospholipid fatty acid composition determined, and hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity assayed. Fish oil diet stimulated cholesterol secretion into bile only after thyroid hormone was given, and this action was synergistic with that of thyroid hormone. Reduced serum cholesterol in fish oil-treated rats was associated with increased biliary cholesterol secretion and diminished hepatic cholesterol content. This suggests that augmented biliary cholesterol secretion may contribute to the fish oil-induced reduction of serum cholesterol. No definite relationship between hepatic or biliary phospholipid fatty acid composition and biliary secretion was apparent, although high bile cholesterol secretion was associated with a low percentage of hepatic and bile phospholipid linoleic acid.     

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

OBJECTIVE: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.     

A study on the relationship between blood lead levels and anemia indicators in workers exposed to low levels of lead

To determine the effects of a vegetarian diet with avocado as a source of monounsaturated fat on serum lipids, thirteen patients with phenotype II (twelve with IIa and one with IIb) dyslipidemia were included in a prospective, transversal and comparative study in which three four-week diets randomly assigned were assessed. One vegetarian diet (ALVD) was composed of 70% carbohydrates, 10% proteins and 20% lipids. Another was composed of 60% carbohydrates, 10% proteins and 30% lipids, 75% of which was supplied by avocado (AVD). A third diet was an avocado-added free diet (FDWA). Body weight, body mass index (BMI), and serum lipids (total cholesterol (TC), high (HDL) and low density lipoprotein (LDL) cholesterol and triglycerides (TG)) were evaluated. AVD produced a significant decrease in LDL. ALVD did not change TC and LDL, while FDWA increased them slightly. The three diets reduced TG levels, but only ALVD did so significantly. All three diets reduced HDL levels, particularly ALVD, which produced the greatest reduction. Low-fat, carbohydrate-rich vegetarian diets may be harmful to hypercholesterolemic patients. The avocado addition to a vegetarian diet does not correct these undesirable effects. To obtain beneficial effects on lipid profile with avocado, lower amounts of carbohydrates and polyunsaturated fatty acids are probably needed.     

Biliary lipid composition in healthy and diseased infants, children, and young adults

Biliary lipid composition and cholesterol saturation were measured in 17 infants and children (age, 4 mo to 9 yr) who had recovered from chronic diarrhea (control subjects), 9 infants and children (age, 4 mo to 9 yr) with interruption of the enterohepatic circulation of bile salts from birth, and in 20 healthy young adults (age, 21-35 yr). The cholesterol molar fraction in pediatric controls was 3.7 +/- 0.2% (mean +/- SE), and in patients with ileal dysfunction or resection was 3.4 +/- 0.4%. Both values were significantly lower than that found in adults (5.7 +/- 0.5%, p less than 0.01). Cholesterol saturation, calculated using the method of Thomas and Hofmann, was significantly reduced in patients with ileal dysfunction or resection (0.60 +/- 0.10; p less than 0.01) and juvenile controls (0.72 +/- 0.04; p less than 0.05) compared with adults (1.08 +/- 0.09). It appears that proportionately larger bile salt pools (adjusted to body size) in both pediatric groups compared with their normal and diseased adult counterparts contribute to the observed reduction in the biliary molar fraction of cholesterol and reduced cholesterol saturation. However, both normal and diseased infants and children primarily have reduced biliary cholesterol/bile salt excretion ratios such that, even at low rates of secretion, bile is not saturated with cholesterol. Therefore, age-related differences in biliary lipid secretory rates seem to produce unsaturated bile in both normal and diseased prepubertal humans.     

Ursodeoxycholic acid treatment in cholesterol gallstone disease: effects on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, biliary lipid composition, and plasma lipid levels

The present study was undertaken to characterize the effects of ursodeoxycholic acid on biliary lipid metabolism in man. Fifteen gallstone patients were treated with ursodeoxycholic acid at a daily dosage of 15 mg per kg body weight for about 4 weeks before cholecystectomy. At operation a liver biopsy, together with gallbladder and hepatic bile, were obtained. Eighteen untreated gallstone patients undergoing cholecystectomy served as controls. During treatment with ursodeoxycholic acid, hepatic bile became unsaturated with cholesterol in all patients investigated. The total biliary lipid concentration remained unchanged. The hepatic cholesterol concentration decreased by about 20%. No significant change in the microsomal HMG CoA reductase activity was observed (38.5 +/- 6.7 pmol . min-1 . mg protein-1 vs 38.3 +/- 4.7 pmol . min-1 . mg protein-1 in the controls; means +/- SEM). Plasma concentrations of total cholesterol were reduced by about 10%, and those of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by about 15%. Plasma triglyceride levels remained essentially unchanged during treatment. We conclude that, similar to chenodeoxycholic acid therapy, ursodeoxycholic acid treatment results in unsaturation of fasting hepatic bile. In contrast to the changes seen during chenodeoxycholic acid feeding, however, the unsaturation of hepatic bile during ursodeoxycholic acid treatment is not primarily related to a decreased hepatic HMG CoA reductase activity. Furthermore, while chenodeoxycholic acid tends to increase plasma LDL levels, such changes are not seen during ursodeoxycholic acid treatment.     

Phospholipase A2 relieves phosphatidylcholine inhibition of micellar cholesterol absorption and transport by human intestinal cell line Caco-2

Cholesterol absorption from bile acid micelles is suppressed by phosphatidylcholine (PC) in the micelles. The effects of micellar phospholipid composition on absorption, metabolism, and secretion of lipids were examined in Caco-2 cells incubated with micelles composed of taurocholic acid, cholesterol, oleic acid, monooleoylglycerol, and phospholipid. Significant amounts of all micelle lipids were absorbed from micelles lacking phospholipid. Cholesterol absorption was accompanied by cholesterol esterification and secretion. Micellar oleic acid was also absorbed and reesterified primarily into triacylglycerol which was also secreted. Lipid absorption and secretion from micelles containing lysophosphatidylcholine (LPC) were similar to that obtained with phospholipid-free micelles. LPC was also extensively absorbed. In contrast, incubations with PC-containing micelles resulted in large reductions in the absorption, esterification, and secretion of cholesterol without significant decreases in oleic acid absorption, conversion to acylated lipids, or triacylglycerol secretion. A relatively small reduction in monoacylglycerol absorption from PC-containing micelles was detected. Retinol absorption was not affected by micellar PC. Substitution of LPC for half or more of the PC reversed the PC-dependent decrease in cholesterol absorption. Pancreatic phospholipase A2 (pPLA2) enhanced cholesterol absorption from PC-containing micelles. The pPLA2-dependent increase in cholesterol absorption was inhibited by the pPLA2 inhibitor FPL 67047XX. The results indicate micellized cholesterol absorption by enterocytes is uniquely dependent on the elimination of micellar phosphatidylcholine and thus directly dependent on the lipolytic action of pancreatic phospholipase A2 (pPLA2). Consequently, pPLA2 inhibitors may be a new and novel class of cholesterol absorption inhibitors for therapeutic use.     

Effect of ethynylestradiol on biliary excretion of bile acids, phosphatidylcolines, and cholesterol in the bile fistula rat

The effects of ethynylestradiol on endogenous bile acids, their capacity to conjugate and excrete intravenously infused cholic acid, the concentrations of biliary cholesterol and lecithin, and the individual molecular species of phosphatidylcholine have been determined in male and female Sprague-Dawley rats. Endogenous biliary bile acids were analyzed by gas-liquid chromatography-mass spectrometry. Eleven bile acids were identified and several minor bile acids, primarily muricholates, could not be completely characterized. After 5 days of treatment with ethynylestradiol (1 mg/kg per day), the percentage of cholic acid decreased and the percentage of 6beta-hydroxylated bile acids, including several monounsaturated species, increased. Ethynylestradiol caused a decrease in bile acid-independent bile flow. Intravenous infusion of cholic acid at a high concentration caused cholestasis in control animals but, after ethynylestradiol treatment, cholestasis developed during the infusion of a much lower concentration of cholate, indicating a lowered threshhold for bile acid-induced cholestasis. In the treated rats, there was a slight increase in excretion of unconjugated endogenous bile acids, and a striking impairment of conjugation of intravenously administered cholic acid. One of the few sex-related differences observed was an increased concentration of biliary phospholipids in untreated male rats. Both phospholipid and cholesterol concentrations in the bile were higher in the treated animals. The molar percentage of cholesterol was always 1-2%, but it was slightly higher in treated animals, especially males. Ethynylestradiol treatment also affected biliary phospholipid by causing a marked increase of phosphatidylcholine species containing palmitic and oleic acid residues and a decrease of species containing stearic and linoleic acid residues. There was no increase in biliary excretion of long chain polyunsaturated species, which might have indicated damage to membranes, in response to ethynylestradiol either alone or with cholic acid infusion. Some of these ethynylestradiol-induced changes in biliary bile acid and lipid excretion are probably peculiar to the rat, but others, such as the increase in molar percentage of cholesterol and cholestasis, may be relevant to disorders in man, especially cholesterol gallstones and idiopathic cholestasis of pregnancy.     

Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism

Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) activity, 39.6 (SEM 2.8) v. 171.0 (SEM 47.3) pmol/min per mg protein. Cholesterol 7 alpha-hydroxylase (EC 1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA:cholesterol acyl transferase (ACAT; EC 2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs 0.72 (P < 0.005), and rs 0.68 (P < 0.01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.     

Biliary cholesterol excretion: a novel mechanism that regulates dietary cholesterol absorption

The regulation of dietary cholesterol absorption was examined in C57BL/6 and transgenic mice with liver overexpression of the scavenger receptor BI (SR-BI Tg). In C57BL/6 animals, feeding 0.02 to 1% (wt/wt) dietary cholesterol resulted in a dose-dependent decrease in the percentage of dietary cholesterol absorbed. A plot of total daily mass of dietary cholesterol absorbed versus the percentage by weight of cholesterol in the diet yielded a curve suggesting a saturable process with a Km of 0.4% (wt/wt) and a Vmax of 0.65 mg cholesterol/g body weight per day. Dietary cholesterol suppressed hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity, stimulated cholesterol 7alpha-hydroxylase activity, and enhanced fecal excretion of bile acids, but none of these changes correlated with the percentage of dietary cholesterol absorption. Dietary cholesterol also caused an increase in biliary cholesterol concentration, and in this case the concentration of biliary cholesterol was strongly and inversely correlated with the percentage dietary cholesterol absorption (r = -0.63, P < 0.0001). Biliary cholesterol concentration was also directly correlated with daily cholesterol intake, dietary cholesterol mass absorption, and liver cholesterol ester content. Transgene-induced overexpression of SR-BI resulted in a stimulation of excretion of cholesterol into the bile and suppressed percentage dietary cholesterol absorption. Furthermore, biliary cholesterol levels in SR-BI Tg mice were strongly and inversely correlated with the percentage of dietary cholesterol absorbed (r = -0.99, P < 0.0008). In summary, these results suggest that the excretion of cholesterol into the bile plays an important role in regulating the percentage absorption of dietary cholesterol.     

Regional ileitis (Crohn's disease). I. Kinetics of bile acid absorption in the perfused ileum

Bile acid absorption was studied by steady state perfusion technique in the ileum of 11 patients with regional ileitis (Crohn's disease). By computerizing absorption kinetics the presence of an active transport of glycochenodeoxycholic acid (GCDC) was rendered probable by finding a saturable transport system and a competitive absorption between conjugated bile acids. At the time of investigation 5 patients had no diarrhoea, whereas 6 patients had diarrhoea as defined from the amount of faecal output. In the former group the faecal bile acid excretion was low, the ileal absorption of GCDC high, and judged from the xylose absorption the ileal absorption surface large compared to the latter group, in which the faecal bile acid excretion was high, the ileal absorption of GCDC low, and the ileal absorptive surface small. It is concluded that malabsorption of bile acids in the ileum may be of significant physiological importance in the pathogenesis of diarrhoea in patients with regional ileitis.     

Nonselective nerve fibre damage in peripheral nerves after experimental thermocoagulation

BACKGROUND: The insoluble material in supersaturated bile is prerequisite for the formation of gallstones. We therefore studied the biliary precipitable and soluble cholesterol and noncholesterol sterols, including the cholesterol precursor sterols (including lanosterol and lathosterols), and the plant sterols campesterol and sitosterol, and cholestanol, which usually reflect cholesterol synthesis and absorption, respectively, before and after a 6-month treatment with ursodeoxycholic acid (UCDA), 15.4 +/- 4 mg/kg/day (standard error of the mean) or simvastatin (40 mg/day) in 21 patients with cholesterol gallstones, to obtain further information about the factors contributing to the formation of gallstones. METHODS: The sediment and supernatant fractions of duodenal bile samples were separated by ultracentrifugation and analyzed with gas-liquid chromatography. RESULTS: At the base line (n = 21) 50% +/- 3% of biliary cholesterol and a variable amount of the noncholesterol sterols (from 14% of lanosterol to 62% of cholestanol) were in the sediment fraction. The pattern of the noncholesterol sterols in the sediment resembled that of gallstones described previously. At base line body mass index was positively related to the percentage of precipitable cholesterol in bile (r = 0.46, P < 0.05), and the serum sitosterol proportion negatively related to the molar percentage of biliary cholesterol and positively to that of bile acids (r = -0.46 and r = 0.50, P < 0.05 for both). UDCA decreased the precipitable percentage of cholesterol from 46% to 31% (P < 0.03) and simvastatin from 57% to 42% (P = 0.05). Both drugs also decreased the precipitable percentages of lathosterols and cholestanol while increasing that of lanosterol. In relation to cholesterol, the sediment to supernatant ratios of all methylsterols were increased, whereas those of polar lathosterols tended to decrease during UDCA treatment. CONCLUSIONS: Patients with high body mass index have more precipitable cholesterol in their bile. Although both UDCA and simvastatin decreased the precipitable cholesterol, the bile still contained one-third of its cholesterol in the sedimentable form.