Biliary Lipid Composition Research Articles

Effect of ethinylestradiol and epomediol on bile flow and biliary lipid composition in rat

Epomediol (1,3,3-trimethyl-2-oxabicyclo(2.2.2.)octan-6,7-endo,endo-diol) (EPO) is a terpenoid compound shown to reverse 17α-ethinylestradiol (EE)-induced cholestasis in rat. The effect is related to the restoration of normal liver plasma membrane fluidity values. To further characterize the effect of EPO, bile flow and biliary lipid composition were measured in rats treated either with EE or EE associated with EPO. EE significantly reduced the bile flow; this reduction was prevented by concomitant treatment with EPO with an increase in the bile salt secretion rate. EPO alone showed a choleretic effect. The biliary secretion rate of cholesterol was also significantly reduced by EE while being comparable to controls in EE-EPO-treated animals. Phospholipid (PL) biliary excretion was significantly (P < 0.002) increased by EE either alone or combined with EPO. After EE treatment, the biliary PL composition showed a reduction in phosphatidylcholine (PC) concentration with a parallel increase in lyso-phosphatidylcholine (LPC) when compared to control animals (PC:LPC ratio 5.0 ± 2.5 vs 26.8 ± 9.9, mean ± SD, P < 0.005). EPO administration to EE-treated rats restored the biliary PC:LPC ratio to control values (27.6 ± 10.6). EPO alone did not show any appreciable effect as compared to both control and EE-EPO treated animals. As increased concentrations of LPC have been reported to induce an alteration in the function of membrane lipids and membrane-associated proteins, such as regulatory enzymes for bile acid, cholesterol and phospholipid metabolism, these results suggest that the protective effect of EPO in EE-induced cholestasis may be related to the reversal of the alterations in membrane lipid composition and function induced by EE.

Effects of ethyl 4-chloro-2-methylphenoxyacetate on bile composition in golden hamsters.

The effects of ethyl 4-chloro-2-methylphenoxyacetate (MCPA) on the cholesterol levels in the liver, serum and gallbladder bile, the composition of both biliary lipids and bile acids, and the hepatic enzyme activities relating to the bile acid formation were investigated in male golden hamsters. MCPA was administered orally to the animals at the doses of 200, 500 and 1,000 mg/kg/day for 2 weeks. Clofibrate (500 mg/kg/day) was also tested for comparison, because of its similarity to MCPA in chemical structure and pharmacological actions. Body weight gain was slightly decreased, but liver to body weight ratio was increased in the MCPA groups of 500 and 1,000 mg/kg and also in the clofibrate group. In these groups, the cholesterol level in the liver was decreased but that in bile was increased. The composition of biliary bile acids was also changed in both the MCPA groups (500 and 1,000 mg/kg) and the clofibrate group, but in a different manner; the levels and proportions of secondary bile acids were increased in the MCPA groups, while those of cholic acid and deoxycholic acid were decreased in the clofibrate group. These results indicate that MCPA and clofibrate may affect cholesterol catabolism differently, although these two compounds contain the same chlorinated phenoxy acid moiety. The increased level of cholesterol in bile might lead to the formation of cholesterol gallstone, which is frequently found in patients with gallbladder cancer. It is inferred that exposure to MCPA could be a risk factor for gallbladder cancer, which was initiated with some chemical carcinogens, because it increased the levels and proportions of both cholesterol and secondary bile acids in bile.

Effects of ileal resection on biliary lipids and bile acid composition in patients with Crohn's disease.

Biliary lipid composition, cholesterol saturation, and bile acid pattern were determined in fasting duodenal bile of 10 patients (four men and six women, mean age 41 years) with Crohn's disease and a history of ileal resection (mean 64 cm). The data were compared with corresponding values in a group of healthy subjects. None of the patients with Crohn's disease had supersaturated bile. Cholesterol saturation was significantly lower in the patients with Crohn's disease than in the healthy subjects. The molar percentage of cholesterol was also lower among the patients but there was no significant difference. The molar percentages of phospholipids and bile acids were normal. Bile acid composition in the patients with ileal resection was characterised by a significant decrease in the deoxycholic acid fraction and a pronounced increase in the ursodeoxycholic acid fraction compared with the healthy subjects. The surprisingly high percentage of ursodeoxycholic acid may contribute to the low degree of cholesterol saturation in bile. Based on these results patients with Crohn's disease should not have an increased risk of cholesterol gall stone formation.

Influence of total lipid concentration, bile salt:lecithin ratio, and cholesterol content on inter-mixed micellar/vesicular (non-lecithin-associated) bile salt concentrations in model bile.

We modified classic equilibrium dialysis methodology to correct for dialysant dilution and Donnan effects, and have systematically studied how variations in total lipid concentration, bile salt (taurocholate):lecithin (egg yolk) ratio, and cholesterol content influence inter-mixed micellar/vesicular (non-lecithin-associated) concentrations (IMC) of bile salts (BS) in model bile. To simulate large volumes of dialysant, the total volume (1 ml) of model bile was exchanged nine times during dialysis. When equilibrium was reached, dialysate BS concentrations plateaued, and initial and final BS concentrations in the dialysant were identical. After corrections for Donnan effects, IMC values were appreciably lower than final dialysate BS concentrations. Quasielastic light scattering was used to validate these IMC values by demonstrating that lipid particle sizes and mean scattered light intensities did not vary when model biles were diluted with aqueous BS solutions of the appropriate IMC. Micelles and vesicles were separated from cholesterol-supersaturated model bile, utilizing high performance gel chromatography with an eluant containing the IMC. Upon rechromatography of micelles and vesicles using an identical IMC, there was no net transfer of lipid between micelles and vesicles. To simulate dilution during gel filtration, model biles were diluted with 10 mM Na cholate, the prevailing literature eluant, resulting in net transfer of lipid between micelles and vesicles, the direction of which depended upon total lipid concentration and BS/lecithin ratio. Using the present methodology, we demonstrated that inter-mixed micellar/vesicular concentrations (IMC) values increased strongly (5 to 40 mM) with increases in both bile salt (BS):lecithin ratio and total lipid concentration, whereas variations in cholesterol content had no appreciable effects. For model biles with typical physiological biliary lipid compositions, IMC values exceeded the critical micellar concentration of the pure BS, implying that in cholesterol-supersaturated biles, simple BS micelles coexist with mixed BS/lecithin/cholesterol micelles and cholesterol/lecithin vesicles. We believe that this methodology allows the systematic evaluation of IMC values, with the ultimate aim of accurately separating micellar, vesicular, and potential other cholesterol-carrying particles from native bile.

Comparative evaluation of chenodeoxycholic and ursodeoxycholic acids in obese patients: Effects on biliary lipid metabolism during weight maintenance and weight reduction

Obesity is a condition associated with an increased frequency of gallstone disease. This study attempted to evaluate the comparative effects of two gallstonedissolving agents, chenodeoxycholic acid and ursodeoxycholic acid, on bile acid metabolism and biliary lipid secretion in obese subjects in order to identify the bile acid of choice in preventing and treating gallstone disease in obesity. Twenty obese subjects (> 120% ideal body wt) were randomly treated with ursodeoxycholic acid (10 mg · kg−1 · day−1 · 1 mo−1) and then with chenodeoxycholic acid (15 mg · kg−1 · day−1 · 1 mo−1) or with chenodeoxycholic acid first and then with ursodeoxycholic acid. Patients 1–10 were studied while eating an unrestricted weightmaintenance diet, whereas patients 11–20 were eating a 1080-kcal/d hypocaloric diet. Biliary lipid composition, cholesterol saturation index, and biliary bile acid pattern were evaluated in all subjects before and after each treatment period; in subjects 6–10 and 16–20, biliary lipid secretion rates and bile acid pool size were also evaluated. Both ursodeoxycholic acid and chenodeoxycholic acid decreased cholesterol outputs and cholesterol saturation index. However, during the weight-maintenance period the decrease induced by chenodeoxycholic acid was not significant. Biliary cholesterol outputs and cholesterol saturation index were always lower during ursodeoxycholic acid administration than during chenodeoxycholic acid therapy. Ursodeoxycholic acid levels during ursodeoxycholic acid administration and chenodeoxycholic acid levels during chenodeoxycholic acid administration increased in bile to 50% and 77%, respectively, of total bile acid levels. Bile acid pool size remained unchanged during chenodeoxycholic acid administration and was significantly reduced by ursodeoxycholic acid administration during the weight-reduction period. In conclusion, ursodeoxycholic acid in obese subjects seems more effective than chenodeoxycholic acid, at least during weight maintenance, in reducing cholesterol saturation of bile. This effect is related to a significant decrease of biliary cholesterol output.

Effect of Silibinin on biliary lipid composition experimental and clinical study

The effect of Silymarin, a natural flavonoid, on biliary lipid composition, was studied in rats and humans. Bile flow, biliary cholesterol, phospholipid and total bile salt concentrations were measured in 23 control rats and in 27 rats treated with Silibinin, the active component of Silymarin, at the dose of 100 mg/kg body weight i.p. (n = 21) or 50 mg/kg body weight i.p. (n = 6) for 7 days. Biliary cholesterol and phospholipid concentrations were significantly reduced after the higher Silibinin dose (60.9 and 72.9% of the control values), whereas bile flow and biliary total bile salt concentration were unchanged. After the lower Silibinin dose all parameters remained unchanged. Total liver cholesterol content was not affected by Silibinin. On the other hand, in vitro determination of rat liver microsomal 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity showed a significant dose-dependent inhibition by Silibinin (0.5-8 mg/kg). Biliary lipid composition was also assayed in four gallstone and in 15 cholecystectomized patients before and after Silymarin (420 mg per day for 30 days) or placebo administration. In both groups, biliary cholesterol concentrations were reduced after Silymarin treatment and the bile saturation index significantly decreased accordingly. These data suggest that Silibinin-induced reduction of biliary cholesterol concentration both in humans and in rats might be, at least in part, due to a decreased synthesis of liver cholesterol.

Effect of dietary ethanol on gallbladder absorption and cholesterol gallstone formation in the prairie dog

Dietary ethanol has been reported to protect against cholesterol gallstone formation. Because enhanced gallbladder absorption of water is important in cholesterol cholelithiasis, we examined the hypothesis that ethanol acts by inhibiting the absorptive function of the gallbladder. Eighteen adult male prairie dogs were fed a lithogenic liquid diet containing 0.4% cholesterol. Half of the animals received 30% of total calories as ethanol, whereas their pair-fed controls received equicaloric amounts of maltosedextrin. After 3 months, the gallbladders were inspected for gallstones and crystals, and gallbladder and hepatic bile were analyzed. Cholesterol stones and crystals were present in all nine controls. None of the alcohol-fed animals had stones, but four had cholesterol crystals. Gallbladder cholesterol, phospholipids, and total calcium were significantly decreased in alcohol-fed animals. In both gallbladder and hepatic bile, the cholesterol saturation index was significantly lower in alcohol-fed animals, as was the ratio of trihydroxy to dihydroxy bile salts. The ethanol-supplemented diet produced a significant decrease in the absorption of water by the gallbladder as indicated by changes in the gallbladder bile to hepatic bile ratios of the total bile salt concentration (7.29 ± 1.25 versus 3.84 ± 0.56; p <0.05) and the total calcium (3.37 ± 0.24 versus 2.43 ± 0.29; p <0.05). These findings indicate that the protective effect of ethanol may be related to its ability both to inhibit gallbladder absorption of water and to alter the composition of biliary lipids.

A simple method for the determination of lipid composition of human bile.

The Entero-Test, a device for easy sampling of gastrointestinal contents, including bile, has been used for determination of biliary lipid composition. The device consists of a weighted gelatin capsule containing 140 cm of a highly absorbent nylon line. The capsule is swallowed while one end of the string is taped to the face. After 3.5 h, when the line has reached the duodenum, gallbladder contraction is stimulated by intramuscular administration of ceruletide. The line is pulled out, and the last 15 cm are eluted four times in methanol. Total bile acids (by 3 alpha-hydroxysteroid-dehydrogenase assay), individual bile acids (by high performance liquid chromatography), phospholipids (by assay of lipid-soluble phosphorus), and cholesterol (by gas-liquid chromatography) are determined in the eluate. Tests in vitro demonstrated no preferential binding and a good recovery of biliary lipids from the thread. Similar values of biliary cholesterol saturation were obtained by means of duodenal intubation and of the Entero-Test in a series of 12 subjects (r = 0.952). In 5 subjects, individual bile acids were also measured and were found to be similar with both techniques (r = 0.948). When the test was repeated over 3 days in a series of 7 subjects, biliary cholesterol saturation was found to be remarkably reproducible (CV = 7.6%). Thus, the Entero-Test is a convenient technique for the determination of biliary lipid composition, which can be particularly useful in longitudinal studies.

Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism.

Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2,021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05), increased biliary cholesterol secretion (P less than 0.005), lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05), altered biliary bile acid composition [( CA + DCA]/CDCA increases, P less than 0.005), stimulated cholesterol esterification (P less than 0.03), and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P less than 0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.

The prevention of cholelithiasis with infused sodium chenodeoxycholate in the prairie dog ( Cynomys ludovicianus)

1. 1. This study examines the efficacy of infused sodium chenodeoxycholate to prevent cholesterol gallstone formation in the prairie dog when fed a high cholesterol diet. 2. 2. Three experimental groups were designed to examine this. The first group ( N = 5) was fed a normal rat chow diet, the second group ( N = 5) was fed a high cholesterol diet (0.4% cholesterol by weight), and the third group ( N = 5) was fed a high cholesterol diet plus given a daily injection of intravenous sodium chenodeoxycholate (15 mg/kg). 3. 3. All of the animals in the second group had cholesterol crystals and cholesterol gallstones. In the third group, none of the animals had gallstones, and all but one lacked cholesterol crystals. 4. 4. Statistical analysis showed that the first and third groups were statistically identical in their lithogenic indices and biliary lipid composition. 5. 5. We concluded that infused sodium chenodeoxyeholate is effective in preventing cholesterol gallstone formation in the prairie dog when fed a high cholesterol diet.

Bile Composition of Adult Baboons Is Influenced by Breast Versus Formula Feeding

SummaryWe tested the hypothesis that infant cholesterol intake and breast‐ versus formula‐feeding influence the bile cholesterol saturation index and bile acid conjugate composition in adult baboons at 7–8 years of age. We also measured the influence of the postweaning intake of dietary cholesterol and fat (saturated and unsaturated) on the effects of the infant diets. The 80 baboons were derived from six sires and 80 dams and randomly assigned at birth to breast‐feeding or to one of three formulas containing about 2, 30, or 60 mg cholesterol/dl. After weaning at 16 weeks of age the animals were assigned to one of four adult diets, which contained 0.01 or 1.0 mg/kcal of cholesterol containing 40% of calories from saturated or unsaturated fat. The bile cholesterol saturation index was significantly higher at 7–8 years of age in baboons breastfed as infants compared with those fed formula (87.0% versus 72.8%, p &lt; 0.004). The cholesterol saturation index was not significantly different among the three formula groups. Among baboons who were breast‐fed and subsequently fed saturated fat as adults, the glycine/ taurine (G/T) ratios of the bile acid conjugates were about three times those of baboons fed unsaturated fat (1.53 versus 0.47); whereas among formula‐fed animals the type of fat did not influence the G/T ratio (interaction, p = 0.022). Adult baboons fed the three formulas in infancy had an inverse relationship of the G/T ratio to the level of formula cholesterol (p &lt; 0.05), We conclude that breastfeeding and formula feeding in infancy differentially affect biliary lipid composition and its response to dietary cholesterol and fat in adulthood. These deferred effects of infant diet on bile lipid composition may influence gallstone formation and intestinal cholesterol and bile acid metabolism.

Bile Composition of Adult Baboons Is Influenced by Breast Versus Formula Feeding

We tested the hypothesis that infant cholesterol intake and breast- versus formula-feeding influence the bile cholesterol saturation index and bile acid conjugate composition in adult baboons at 7-8 years of age. We also measured the influence of the postweaning intake of dietary cholesterol and fat (saturated and unsaturated) on the effects of the infant diets. The 80 baboons were derived from six sires and 80 dams and randomly assigned at birth to breast-feeding or to one of three formulas containing about 2, 30, or 60 mg cholesterol/dl. After weaning at 16 weeks of age the animals were assigned to one of four adult diets, which contained 0.01 or 1.0 mg/kcal of cholesterol containing 40% of calories from saturated or unsaturated fat. The bile cholesterol saturation index was significantly higher at 7-8 years of age in baboons breast-fed as infants compared with those fed formula (87.0% versus 72.8%, p less than 0.004). The cholesterol saturation index was not significantly different among the three formula groups. Among baboons who were breast-fed and subsequently fed saturated fat as adults, the glycine/taurine (G/T) ratios of the bile acid conjugates were about three times those of baboons fed unsaturated fat (1.53 versus 0.47); whereas among formula-fed animals the type of fat did not influence the G/T ratio (interaction, p = 0.022). Adult baboons fed the three formulas in infancy had an inverse relationship of the G/T ratio to the level of formula cholesterol (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Characteristics of biliary lipid metabolism after liver transplantation

Biliary lipid metabolism was studied after 10 liver transplantations with continuous drainage of bile. Within 3 wk after transplantation, the new liver produced bile with concentrations of biliary lipids in agreement with those reported for T-tube bile in cholecystectolized nontransplanted subjects. Although changes in biliary lipid composition occurred swiftly in response to various forms of disturbed liver function, they did not provide substantially more information than did standard serum tests or simple measurements of bile flow in most patients. Secretion rates of phospholipids and cholesterol were found to be completely bile acid dependent. For each micromole of bile acids, 0.22 and 0.08 mumol of phospholipids and cholesterol were secreted, respectively. When bile flow was related to bile acid output, a linear relationship was found (r = 0.89), with a positive intercept indicating a bile acid-independent bile flow of approximately 44 microliters/min. Analysis of individual bile acids showed almost exclusively primary bile acids. The relative proportion of chenodeoxycholic acid was more prominent during the first days after transplantation. Different explanations for this are discussed.

The effects of ethinylestradiol, a glucose diet and streptozotocin induced diabetes mellitus on gallstone formation and biliary lipid composition in the hamster

Possible risk factors for gallstone formation were examined and the concentrations of biliary lipids and each bile acid in the hepatic and gallbladder bile of hamsters were quantified. Forty female golden Syrian hamsters were divided into 4 groups according to diet; Group I, given control chow, Group II, given an ethinylestradiol and cholesterol supplemented diet, Group III, given a glucose rich diet without induced diabetes mellitus, and Group IV, given a glucose rich diet with diabetes mellitus induced by streptozotocin injection. The formation of cholesterol crystals but not gallstones was induced in Group II associated with a significantly decreased total bile acid concentration in the gallbladder bile but not in the hepatic bile. The formation of cholesterol gallstones and crystals with significantly higher concentrations of cholesterol and phospholipid was observed in Group III, while neither the formation of gallstones nor lithogenicity was enhanced by diabetes mellitus. However, a quite different lithogenicity was evident between the hepatic and gallbladder bile of the Group IV animals. These results suggest that neither the consumption of oral contraceptives nor diabetes mellitus induces gallstone formation, but that these factors can be responsible for dysfunction of the gallbladder.

Early effects of colectomy and endorectal pullthrough operation on biliary lipid composition

In order to determine the effects of total colectomy and endorectal pullthrough with ileal reservoir (ERP) on biliary lipid composition in the early postoperative period, gallbladder bile of dogs was examined after biliary cannulation alone (control); biliary cannulation and colectomy with ileorectal anastomosis (IRA); and biliary cannulation, colectomy with mucosal proctectomy, and ERP. Bile collected from 3 to 6 weeks postoperation was analyzed for total bile acids, cholesterol, phospholipids, bilirubin, and calcium concentrations. Cholesterol saturation was calculated. Serum collected over the same period was analyzed for electrolytes and liver function tests. There was no evidence of sludge or gallstones postoperatively in any animal. Significant decreases in total bile acids, phospholipids, and calcium concentrations were noted in the bile of the IRA group when compared to the bile of the controls ( P < 0.05) and in total bile acids, cholesterol, phospholipids, and calcium in ERP vs controls ( P < 0.05). Moreover, all three biliary lipids and calcium were significantly decreased in ERP animals compared to those in the IRA group ( P < 0.05). No change in cholesterol saturation was noted between any of the three groups. Other than an increase in alkaline phosphatase concentrations compared to preoperative levels ( P < 0.05) which was noted in all groups, no significant changes were noted in serum parameters. We conclude that during the early postoperative period, ERP causes a significant decrease in gallbladder bile concentrations of total bile acids, cholesterol, phospholipids, and calcium which cannot be explained by colectomy alone. The longterm effects on biliary composition remain to be defined.

Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat

The present study concerns short- and long-term effects of interruption of the enterohepatic circulation (EHC) on hepatic cholesterol metabolism and biliary secretion in rats. For this purpose, we employed a technique that allows reversible interruption of the EHC, during normal feeding conditions, and excludes effects of anaesthesia and surgical trauma. [3H]Cholesteryl oleate-labelled human low-density lipoprotein (LDL) was injected intravenously in rats with (1) chronically (8 days) interrupted EHC, (2) interrupted EHC at the time of LDL injection and (3) intact EHC. During the first 3 h after interruption of the EHC, bile flow decreased to 50% and biliary bile acid, phospholipid and cholesterol secretion to 5%, 11% and 19% of their initial values respectively. After 8 days of bile diversion, biliary cholesterol output and bile flow were at that same level, but bile acid output was increased 2-3-fold and phospholipid output was about 2 times lower. The total amount of cholesterol in the liver decreased after interruption of the EHC, which was mainly due to a decrease in the amount of cholesteryl ester. Plasma disappearance of LDL was not affected by interruption of the EHC. Biliary secretion of LDL-derived radioactivity occurred 2-4 times faster in chronically interrupted rats as compared with the excretion immediately after interruption of the EHC. Radioactivity was mainly in the form of bile acids under both conditions. This study demonstrates the very rapid changes that occur in cholesterol metabolism and biliary lipid composition after interruption of the EHC. These changes must be taken into account in studies concerning hepatic metabolism of lipoprotein cholesterol and subsequent secretion into bile.

Biliary lipids in familial combined hyperlipidaemia: effects of acipimox therapy

Biliary lipid composition and plasma lipoprotein levels were determined in nine gallstone-free male patients with familial combined hyperlipidaemia (FCHL). In the basal situation, stimulated fasting duodenal bile from the patients contained a higher relative concentration of cholesterol than bile obtained from age- and sex-matched normal controls (n = 22), 6.5 +/- 0.3 (SEM) vs. 4.7 +/- 0.2 mol % (P less than 0.01). This resulted in a higher cholesterol saturation of bile from FCHL patients, 85 +/- 6 vs. 70 +/- 2% (P less than 0.05). After 6 weeks of treatment with acipimox, 750 mg day-1, total plasma triglycerides were lowered from 7.5 +/- 1.5 to 4.6 +/- 0.7 mmol l-1 (P less than 0.05) and plasma cholesterol decreased from 8.0 +/- 0.1 to 7.1 +/- 0.3 mmol l-1 (P less than 0.05) in the FCHL patients. These changes were mainly due to a decrease in very low density lipoprotein concentrations while low density lipoprotein levels remained unaltered. The relative proportion of cholesterol in stimulated fasting duodenal bile was reduced from 6.5 +/- 0.3 to 4.3 +/- 0.5 mol % (P less than 0.01), resulting in 'normalization' of biliary cholesterol saturation, from 85 +/- 6 to 58 +/- 6% (P less than 0.005). No correlations between the changes in biliary lipid composition and those in plasma lipoprotein levels were observed. The results indicate that treatment with acipimox in patients with FCHL, a disorder commonly associated with supersaturated bile, does not increase biliary cholesterol, and presumably not the risk for gallstone formation.

Bile acid metabolism in familial dysbetalipoproteinaemia: studies in subjects with the apolipoprotein E‐2/2 phenotype

Bile acid kinetics and biliary lipid composition were determined in seven subjects with primary dysbetalipoproteinaemia. They were all homozygous for the apolipoprotein E isoform E-2 and six of them were hyperlipidaemic (type III hyperlipoproteinaemia). With or without hyperlipidaemia, the apo E-2/2 phenotype was associated with increased bile acid formation (mean increase compared with 32 normolipidaemic controls, 43%; P less than 0.025). The biliary lipid composition was not different from that seen in the controls. The results indicate that the uptake by the liver of apo E-containing remnant particles is of importance for the regulation of hepatic cholesterol metabolism in man. It is suggested that hepatic cholesterol synthesis is stimulated in dysbetalipoproteinaemia, and that this leads to a compensatory increase in bile acid synthesis.

Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia.

Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p less than 0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p less than 0.01) from 1.06 to 0.75 during treatment with pravastatin. A reduction of 24% (p less than 0.01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gall stones.

Effect of Chronic Ursocholic Acid Administration on Bile Lipid Composition and Bile Acid Pool Size in Gallstone Patients

We assessed the effect of chronic (4-6 weeks) administration of ursocholic acid (UCA) (15 mg/kg/day), a natural bile acid with poor detergent capacity, on biliary lipid composition of gallbladder bile (n = 26) and bile acid pool size (n = 5) in gallstone patients. During treatment the biliary molar percentage UCA increased from trace values to 28% (p less than 0.001). This effect was accompanied by an increase in molar percentage deoxycholic acid from 16% to 33% (p less than 0.001). Total bile acid pool size remained unchanged during UCA administration; cholic acid and chenodeoxycholic acid pool sizes decreased from 1.0 to 0.6 mmol (p less than 0.05) and from 1.6 to 0.9 mmol (p less than 0.05), respectively. The molar percentage cholesterol of gallbladder bile decreased from 9.8% to 7.0% (p less than 0.001) during UCA, but bile remained supersaturated with cholesterol in 21 patients. The weak effect on biliary lipid composition and the increase of potentially toxic deoxycholic acid in bile suggest that UCA is unlikely to replace ursodeoxycholic and chenodeoxycholic acid for medical treatment of gallstones.