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PubMed1988

Bile and bile salts potentiate superoxide anion release from activated, rat peritoneal neutrophils.

Certain bile salts cause hepatotoxicity as well as injury to extrahepatic organs when administered to animals. Activated neutrophils (PMNs) may cause tissue injury by releasing reactive oxygen species and other products. Since PMNs may come in contact with biliary components, such as bile salts, following chemical insult to the liver or during cholestasis, we examined the capacity of bile and bile salts to stimulate superoxide anion (O2-) release from rat peritoneal PMNs in vitro. Neither bile nor bile salts, with the exception of lithocholate, could by themselves stimulate O2- release from PMNs. Lithocholate (32 microM) caused small but statistically significant release of O2- from PMNs. When PMNs were primed with a barely suprathreshold concentration of 12-O-tetradecanoyl-phorbol-13-acetate (PMA), a classic stimulus for PMNs, the addition of bile and certain bile salts markedly enhanced O2- release from PMNs. The monohydroxy bile salt, lithocholate, had the greatest stimulatory activity toward PMA-primed PMNs, causing approximately an eightfold increase in O2- release. The enhancing effect of lithocholate was maximal between 10 and 32 microM, and it also occurred with PMNs isolated from rat blood. Dihydroxy bile salts, deoxycholate and chenodeoxycholate (100 microM), caused more modest enhancement of O2- release (two- to threefold) from primed PMNs. Cholate, a trihydroxy bile salt, was not active at these concentrations. Conjugation of either lithocholate or chenodeoxycholate with either glycine or taurine markedly reduced the ability of the bile salt to enhance O2- release from primed PMNs. Structural alterations on the hydrophilic side chain or within the planar, hydrophobic portion of the bile salt molecule reduced the capacity to enhance O2- release from PMA-primed PMNs. These results indicate that bile salts can potentiate the respiratory burst in PMNs and suggest a role for this interaction in toxicoses or disease states characterized by elevated serum bile salts.

Animals↗
PubMed1985

Influence of side-chain charge on hepatic transport of bile acids and bile acid analogues.

The importance of side-chain charge on hepatic uptake and biliary secretion of bile acids and analogues was studied using the isolated, perfused rat liver and the anesthetized rat with a bile fistula. Derivatives of cholic acid with negative, neutral, zwitterionic, or positive charges on the side chain were synthesized and studied. Hepatic uptake by the isolated perfused liver, determined by measuring the rate of disappearance of a single 20-mumol bolus added to the perfusate, was strongly influenced by side-chain charge. A fully positively charged bile acid derivative (cholylcholamine) and two fully zwitterionic bile acid derivatives (CHAPS and cholyllysine) showed no appreciable uptake (less than 1% of the uptake rate of cholyltaurine). Bile acid derivatives existing mostly in cationic form (cholylamine) at pH 7.4, in neutral form (cholylglycylhistamine), or in divalent anion form (cholylaspartate and cholylcysteate) had an uptake rate that was greater but only 7-19% that of cholyltaurine. Side-chain charge also appeared to influence the rate of secretion into bile. Bile acids existing in mono- or dianionic form were well secreted (greater than 95% of dose in 2 h) into the bile, but all other derivatives had much lower secretion rates (less than 20% of dose in 2 h). When the biliary secretion of each bile acid derivative was expressed in relation to the amount that had entered the liver, relative secretion rates (presumably from liver cell) into bile decreased in the following order: cholyltaurine greater than cholylaspartate and cholylcysteate greater than CHAPS greater than cholyllysine greater than cholylglycylhistamine approximately equal to cholylamine. In bile fistula rats, cholylaspartate was quantitatively secreted into bile when infused at rates below its secretory maximum, whereas only very low biliary secretion rates of CHAPS were observed even during relatively high infusion rates; cholylamine was cholestatic. The above data show that, although uncharged and anionic derivatives of cholic acid may be taken up by the liver at a moderate rate, only anionic derivatives (both monovalent and divalent) are well secreted from within the liver cell into bile. A single negative charge on the side chain appears to be required for optimal transport of a bile acid from sinusoidal blood to bile.

Animals↗
PubMed1992

Bile salt hydrophobicity controls vesicle secretion rates and transformations in native bile.

After drainage of the bile salt pool, we infused unanesthetized bile fistula prairie dogs (Cynomys ludovicianus) intravenously with taurine-conjugated chenodeoxycholate (TCDC), cholate (TC), ursodeoxycholate (TUDC), and ursocholate (TUC) in concentrations that attained greater than 94% enrichment of biliary bile salts. With decreases in bile salt hydrophobicity, maximum steady state lecithin and to a lesser extent cholesterol secretion rates decreased in the rank order, TCDC greater than TC greater than TUDC greater than TUC. By phase analysis, TCDC-rich and TC-rich biles plotted inside their respective micellar zones, whereas TUDC-rich and TUC-rich biles plotted outside and were so-called "supersaturated" with cholesterol. Quasi-elastic light scattering and electron microscopy, when performed within 30 min of collection, revealed unilamellar vesicles in all biles. By 24 h, vesicles in TCDC-rich and TC-rich biles had dissolved into mixed micelles, whereas vesicles in TUDC-rich biles formed mixed micelles plus multilamellar liquid crystals, and vesicles in TUC-rich biles formed multilamellar liquid crystals exclusively. Because cholesterol/phospholipid molar ratios of multilamellar liquid crystals were less than or equal to 1, cholesterol monohydrate crystals did not form in these biles. We conclude that, despite drastic alterations in bile salt detergency, unilamellar vesicles are the final common pathway for lecithin and cholesterol secretion into bile. During equilibration of bile, the fate of unilamellar vesicles may be micellar, micellar plus liquid crystalline, or liquid crystalline only depending on the detergency (i.e., hydrophobic-hydrophilic balance) of the secreted bile salt.

Absorption↗
PubMed1993

Is duodenal bile representative of gallbladder bile? A comparative study.

Thirty-nine patients with cholelithiasis were prospectively studied to evaluate the qualitative and quantitative differences between duodenal bile and gallbladder bile. Duodenal bile obtained before cholecystectomy by nasoduodenal intubation and ceruletide injection was qualitatively similar to gallbladder bile obtained during surgery. Microscopic cholesterol crystals as an indicator of cholesterol gallstones (n = 35) could be detected in 31 (89%) and 35 (100%; p = NS), respectively. Moreover, there was no difference in the molar percentage of three biliary lipids and the mean cholesterol saturation index (1.54 +/- 0.72 and 1.74 +/- 0.42; p = NS) of the two sources of bile. Duodenal bile was, however, dilute as compared with gallbladder bile, as evidenced by lower cholesterol crystal counts (167 +/- 247 versus 705 +/- 978; p < 0.01), lower total lipid concentration (5.8 +/- 2.7 versus 11.1 +/- 5.6 g/dl; p < 0.001), and lower concentrations (in mmol/l) of the three bile lipids--that is, total bile acids, phospholipids and cholesterol (p < 0.001). Good concentrated bile (total lipid concentration > or = 5 g/dl) could be obtained in 74% of duodenal bile samples, compared with 90% of gallbladder bile (p = NS). Our study shows that, although duodenal bile is dilute as compared with gallbladder bile, it is qualitatively similar to gallbladder bile and, because of the ease and safety of its collection, can be used to study serial alterations in biliary composition in individual subjects.

Adult↗
PubMed1986

Identification of unconjugated bile acids in human bile.

Unconjugated bile acids in the bile of healthy and diseased humans were determined qualitatively and quantitatively by means of gas-liquid chromatography and gas-liquid chromatography-mass spectrometry, after their isolation by ion-exchange chromatography. In a healthy person and three patients with cholelithiasis, unconjugated bile acids comprised 0.1-0.4% of total biliary bile acids. The bile acid composition of the unconjugated fraction was quite different from that of the glycine- or taurine-conjugate fraction, in that it contained a relatively large proportion of unusual bile acids including C23 and C27 bile acids. In two patients with cerebrotendinous xanthomatosis, C22 and C23 bile acids were the major constituents of the biliary unconjugated bile acids, and comprised about 0.8% of total bile acids; no detectable amounts of C27 bile acids were found in their bile. The analysis of biliary unconjugated bile acids may be useful for the diagnosis of metabolic diseases concerning bile acids, particularly the accumulation or disappearance of unusual bile acids.

Adult↗
PubMed1981

Chronic bile exposure increases resistance of canine gastric mucosa to bile.

Because four successive weekly exposures of the gastric mucosa of intact dogs to bile did not alter the appearance or the barrier function of the mucosa during subsequent challenges with bile, the effects of chronic continuous exposure to bile were tested. This was accomplished by diversion of the flow of bile from the duodenum into the stomach by cholecystogastrostomy and diversion of the common bile duct. After four weeks, on endoscopic examination the mucosa was dark red but covered in some areas by a creamy coloured, strongly adherent pseudomembrane. Histologically the mucosa was normal. Ion fluxes, when an acid test solution was used, were close to normal. Differences between control dogs and those with chronic bile diversion became very evident, however, when the mucosa was exposed to increasing concentrations of bile. The control dogs displayed increases in net fluxes of H+, Na+, Cl- and K+ as the concentration of the bile was increased but the dogs with chronic bile diversion did not. Also the changes in PD and fluxes in K+ were less in the dogs with bile diversion. In the intact control dogs bile placed in the stomach always produced bleeding and hemorrhagic erosion; in the dogs with chronic bile diversion added bile in the stomach never caused bleeding and the mucosa appeared normal on endoscopic and histological examination. We conclude that the resistance of the gastric mucosa to the barrier breaking action of bile was increased in the dogs with chronic gastric bile diversion.

Animals↗
PubMed1978

[Effect of phenobarbital and chlorpromazine on bile flow and bile acid excretion in male Wistar rats].

Bile flow and excretion of monohydroxy-, dihydroxy- and trihydroxy-bile acids (MBA, DBA and TBA) were estimated after acute and subacute phenobarbital and chlorpromazine pretreatment in 60-day-old male Wistar rats. Bile was collected in bile-fistula rats in three 1-hour periods. MBA were not detected. Neither single nor repeated ip. administration of different amounts of saline before bile sampling nor oral water supply within the bile collection period influenced the bile flow and excretion of DBA and TBA. Phenobarbital administration (60 mg/kg b.w. ip.) 2 hrs before bile sampling did not influence bile flow and bile acid (BA) excretion. After 3 days pretreatment with phenobarbital (3 X 60 mg/kg b.w. ip.) the bile flow was somewhat increased, BA-excretion was unchanged and the relation TBA/DBA diminished. Chlorpromazine administration (40 mg/kg b.w. ip.) 1,5 hrs before bile sampling decreased bile flow and BA excretion within the first collection period, whereas bile flow and BA excretion increased in the thrid collection period. No signs of cholestasis were observed after chlorpromazine pretreatment once a day for 3 days. Bile flow and BA excretion were increased and the relation TBA/DBA was unchanged.

Animals↗
PubMed1980

Occurrence of bile alcohol glucuronides in bile of patients with cerebrotendinous xanthomatosis.

Using thin-layer chromatography, bile alcohol glucuronides were found with taurine- and glycine-conjugated bile acids in the bile of four patients with cerebrotendinous xanthomatosis. The concentration of the bile alcohol glucuronides was 1.7-5.2 times higher than that of the conjugated bile acids. Detectable amounts of unconjugated bile alcohols were not found in the bile of these patients. The bile alcohol glucuronides were isolated from the bile of one of the patients by means of preparative thin-layer chromatography. Treatment with beta-glucuronidase of the bile alcohol glucuronides liberated glucuronic acid and a mixture of bile alcohols. More than 90% of the liberated bile alcohols was 5 beta-cholestane-3 alpha, 7 alpha, 25-tetrol, and lesser amounts of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol, and 5 beta-cholestane-3 alpha,-7 alpha, 12 alpha, 24 alpha, 25-pentol were also obtained. The bile alcohol glucuronides were not oxidized by the treatment with 3 alpha-hydroxysteroid dehydrogenase, indicating that the glucuronide moiety was at 3 alpha-hydroxyl position of the bile alcohols. Comparison of the mass spectra of the acetylated and methylated derivatives of the natural glucuronides and the synthetic 7 alpha, 12 alpha, 25-triacetoxy-5 beta-cholestan-3 alpha-O-(methyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosyluronate) also indicated that the bile alcohol glucuronides consisted of mainly 5 beta - cholestane - 3 alpha, 7 alpha, 12 alpha, 25 - tetrol - glucuronide.

Adult↗
PubMed1993

Mechanism of biliary lipid secretion in the rat: a role for bile acid-independent bile flow?

Bile acid-induced lipid secretion was compared in unanesthetized normal control and Groningen Yellow Wistar rats during variations in endogenous bile acid output. Groningen Yellow rats express a genetic defect in the biliary secretion of various organic anions. During a 5-hr period after interruption of the enterohepatic circulation, bile acid secretion decreased from 36.4 +/- 1.8 to 1.9 +/- 0.3 mumol per 30 min in normal control rats and from 37.1 +/- 2.8 to 1.8 +/- 0.2 mumol per 30 min in Groningen Yellow rats, respectively (mean +/- S.E.M., n = 5). The relationship between bile acid secretion and bile flow showed similar slopes (normal control, 8.74 +/- 0.44 microliter/mumol and Groningen Yellow rats, 7.71 +/- 0.42 microliter/mumol) but different y-intercepts (normal control, 243 +/- 8 and Groningen Yellow, 127 +/- 4 microliters per 30 min; p < 0.001), corresponding to a 47% reduction of the bile acid-independent fraction of bile flow in Groningen Yellow rats. During the course of the experiment, the ratio of lipids (phospholipids plus cholesterol) to bile acids increased in both strains more than threefold but was permanently higher in Groningen Yellow than in normal control rats (p = 0.035), implying that Groningen Yellow rats continuously secreted more lipid per bile acid. No differences in bile acid pool composition or in bile canalicular membrane composition and fluidity between the two strains were detected. The results indicate that apart from previously demonstrated factors (bile acid concentration, bile acid composition and hydrophilic organic anion concentration in bile), another parameter affects the efficacy of bile acids to induce biliary lipid secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Influence of bile flow obstruction vs bile diversion on pancreatic secretion in the conscious rat.

Changes in pancreatic exocrine functions were compared between conscious rats with bile duct ligation and bile diversion from the duodenum on the first, third, fifth, and seventh postoperative days. Body weight was significantly decreased with time in both groups. Basal secretions of fluid, bicarbonate, and protein remained unchanged throughout the experimental period in bile duct ligated rats, whereas in bile diverted rats, the basal bicarbonate secretion with returning of pancreatic juice to the duodenum increased on the third postoperative day, and the basal protein output significantly increased with time. Basal secretions with returning of pancreatic juice to the duodenum in both groups were higher than that in control (bile and pancreatic juice returned to the intestine) rats. Stepwise increases in fluid and bicarbonate outputs responding to the graded doses of secretin were observed in bile duct ligated rats on the first and third postoperative days, as has been observed in bile diverted rats. However, on the fifth and seventh postoperative days, stepwise responses to graded doses of secretin were no longer observed in bile duct ligated rats. The pancreatic response to cerulein was greater in bile diverted rats than in bile duct ligated rats. Plasma CCK concentration in 7-d bile duct ligated rats (4.7 pM) was significantly higher than that in 7-d bile diverted rats (1.6 pM), although the pancreatic wet weight, protein concentration, and total content were comparable for the two groups. It was suggested that the presence of bile in the duodenum is required to maintain normal pancreatic secretion, and that the removal of bile from the intestine has quite different effects, depending on whether the bile flow is obstructed or diverted.

Analysis of Variance↗
PubMed2003

The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors.

The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis.

Bile Acids and Salts↗
PubMed2002

Endoscopic ultrasound-guided gallbladder bile aspiration in idiopathic pancreatitis carries a significant risk of bile peritonitis.

BACKGROUND: Direct microscopic examination of bile for the presence of microlithiasis is often performed during the evaluation of patients with idiopathic pancreatitis. Bile sampled from the duodenum and/or the common bile duct may not represent gallbladder bile, and thus may be inadequate for the diagnosis of microlithiasis. AIM: We sought to determine the safety and efficacy of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of gallbladder bile in patients with idiopathic pancreatitis. METHODS: Patients with idiopathic pancreatitis underwent EUS with a linear echoendoscope. After excluding potential causes of pancreatitis such as common bile duct stones or pancreatic lesions, the gallbladder was identified. The gallbladder lumen was entered using a 22-gauge FNA needle via the duodenal wall. Bile was aspirated and analyzed for the presence of cholesterol monohydrate crystal, calcium bilirubinate granules, calcium carbonate microspheroliths and mucin gel strands. RESULTS: Three patients underwent EUS-guided FNA of gallbladder bile. Two of these patients developed bile peritonitis within one hour of the procedure prompting us to discontinue the study. One patient's gallbladder bile contained microlithiasis. This patient had bile aspirated from the common bile duct via ERCP 3 weeks prior to EUS. However, analysis of that bile sample failed to show microlithiasis. CONCLUSION: Unfortunately, transduodenal EUS-guided FNA of gallbladder bile using a 22-gauge needle carries a significant risk of bile peritonitis.

Acute Disease↗
PubMed2004

Differential expression of cholangiocyte and ileal bile acid transporters following bile acid supplementation and depletion.

AIM: We have previously demonstrated that cholangiocytes, the epithelial cells lining intrahepatic bile ducts, encode two functional bile acid transporters via alternative splicing of a single gene to facilitate bile acid vectorial transport. Cholangiocytes possess ASBT, an apical sodium-dependent bile acid transporter to take up bile acids, and t-ASBT, a basolateral alternatively spliced and truncated form of ASBT to efflux bile acids. Though hepatocyte and ileal bile acid transporters are in part regulated by the flux of bile acids, the effect of alterations in bile acid flux on the expression of t-ASBT in terminal ileocytes remains unclear. Thus, we tested the hypothesis that expression of ASBT and t-ASBT in cholangiocytes and ileocytes was regulated by bile acid flux. METHODS: Expression of ASBT and t-ASBT message and protein in cholangiocytes and ileocytes isolated from pair-fed rats given control (C) and 1% taurocholate (TCA) or 5% cholestyramine (CY) enriched diets, were assessed by both quantitative RNase protection assays and quantitative immunoblotting. The data obtained from each of the control groups were pooled to reflect the changes observed following TCA and CY treatments with respect to the control diets. Cholangiocyte taurocholate uptake was determined using a novel microperfusion technique on intrahepatic bile duct units (IBDUs) derived from C, TCA and CY fed rats. RESULTS: In cholangiocytes, both ASBT and t-ASBT message RNA and protein were significantly decreased in response to TCA feeding compared to C diet. In contrast, message and protein of both bile acid transporters significantly increased following CY feeding compared to C diet. In the ileum, TCA feeding significantly up-regulated both ASBT and t-ASBT message and protein compared to C diet, while CY feeding significantly down-regulated message and protein of both bile acid transporters compared to C diet. As anticipated from alterations in cholangiocyte ASBT expression, the uptake of taurocholate in microperfused IBDUs derived from rats on TCA diet decreased 2.7-fold, whereas it increased 1.7-fold in those on CY diet compared to C diet fed groups. CONCLUSION: These data demonstrate that expression of ASBT and t-ASBT in cholangiocytes is regulated by a negative feedback loop while the expression of these transporters in terminal ileum is modified via positive feedback. Thus, while transcriptional regulatory mechanisms in response to alterations in bile acid pool size are operative in both cholangiocytes and ileocytes, each cell type responds differently to bile acid supplementation and depletion.

Alternative Splicing↗
PubMed1975

Sulfated and nonsulfated bile acids in urine, serum, and bile of patients with hepatobiliary diseases.

Large amounts of bile acid sulfate were found in the urine of patients with hepatobiliary diseases. In patients with acute hepatitis, daily excretion of bile acid into urine was 68.24 plus or minus 51.80 mumoles per day, and the percentage of sulfated bile acid was 83.4 plus or minus 16.7%. In patients with chronic hepatitis and cirrhosis, a slight increase of urinary bile acid was observed (2.89 plus or minus 2.69 and 5.27 plus or minus 4.28 mumoles per day, respectively), and the percentage of sulfated bile acid was 73.9 plus or minus 28.6 and 44.6 plus or minus 30.4%, respectively. In patients with obstructive jaundice, a moderate increase of urinary bile acid was found (32.62 plus or minus 18.35 mumoles per day), and the percentage of sulfated bile acid was 58.3 plus or minus 22.6%. In patients with hepatobiliary diseases, the elevation of both levels of sulfated and nonsulfated bile acids in serum was observed. The percentage of sulfated bile acid was 9% in normal serum, and varied from zero to 82.8% in pathological sera. A remarkable increase of sulfated bile acid was found in patients with obstructive juandice and acute hepatitis, while a slight elevation was found in patients with chronic hepatitis and cirrhosis. Sulfated bile acid in bile was nonexistent or below 0.5% of total bile acid. According to these findings, the increased bile acid in serum of patients with hepatobiliary diseases might be more easily excreted into the urine as sulfated bile acid.

Bile Acids and Salts↗
PubMed1975

The effect of bile acid synthesis on cholesterol secretion into the bile.

Cholesterol secretion into the bile has been shown to be related to the bile acid secretion rate. It has been suggested that the availability of bile acid micelles controls the entry of cholesterol into the bile. However, previous data could have been interpreted to indicate that bile acid synthesis controls cholesterol secretion into the bile. To discover whether bile acid synthesis has a significant influence on cholesterol secretion, Rhesus monkeys were studied during the period of increasing bile acid secretion and bile acid synthesis, which begins 6-10 hours following interruption of the enterohepatic circulation of bile acids. This is the only condition in which bile acid synthesis and bile acid secretion increase simultaneously. The cholesterol secretion rate fell signficantly during this period, and this effect was enhanced by phenobarbital administration. An increasing cholesterol secretion rate would have been expected if micellar attraction controlled cholesterol secretion under these conditions. Bile acid synthesis appears to have an important influence upon cholesterol secretion into the bile.

Animals↗
PubMed1993

Description and simulation of a multiple mixing tank model to predict the effect of bile sequestrants on bile salt excretion.

A nonlinear, multicompartment mixing tank model based on human physiologic parameters from the literature and in vitro bile salt sequestrant binding parameters was integrated numerically to simulate bile salt excretion. The model focuses on the transit of bile salts and resin, bile salt binding, and bile salt reabsorption as a means of gaining insight into the functioning of bile sequestrants in the gastrointestinal tract and the effect of reabsorption of bile salts on the sequestering process. The series of compartments through the ileal region were tested over a range of parameter values, and the results were compared with bile salt output from ileostomy patient data to validate the model without resin. In simulations incorporating resin with a reversible binding scheme, fecal bile salt output was 2.37 (+/- 0.6) x 10(-3) mol/day compared with 2.64 (+/- 1.1) x 10(-3) mol/day for human data. Assuming irreversible bile salt binding resulted in predictions of fecal bile salt excretion greater than three times physiologic values. The results of these simulations support the hypothesis that the lack of efficacy of bile sequestrants is due to the displacement of bound bile salts from the sequestrant as a consequence of anion competition and bile salt reabsorption. Gastric emptying effects and the timing of resin doses have also been investigated with the model.

Bile↗
PubMed1999

Cholesterol enhances membrane-damaging properties of model bile by increasing the intervesicular-intermixed micellar concentration of hydrophobic bile salts.

UNLABELLED: Bile salts are potent detergents that, at concentrations attained in bile and intestine, can disrupt cell membranes. Hepatic secretion of vesicles containing lecithin and cholesterol appears to be critical in preventing bile salt damage to hepatobiliary epithelia. We hypothesize that the protective effect of biliary lipids results from lowering of the bile salt intervesicular intermixed micellar bile salt concentration (IMMC) to which epithelial membranes are exposed. We further hypothesize that increases in biliary cholesterol, by reducing association of bile salts with vesicles and mixed micelles, may increase bile toxicity by raising the bile salt IMMC. METHOD: Large unilamellar lecithin vesicles (100 nm) with varying cholesterol:lecithin molar ratios (C:L) of 0, 0.5, and 1 were added to taurochenodeoxycholate (TCDCA), taurocholate (TCA), or taurodeoxycholate (TDCA) in Tris-buffered saline, pH 7.4. Human erythrocyte ghosts (model target membrane), prepared by osmotic hemolysis and resealed with [14C]inulin trapped inside, were added and incubated at 37 degrees C for 30 min and 4 h. Plasma membrane disruption was quantified by [14C]inulin release and bile salt IMMC was determined by ultrafiltration. RESULTS: Membrane disruption started at a concentration of 0.5 mM for TDCA, 1 mM for TCDCA, and 2 mM for TCA and was complete within 4 h at concentrations of 1, 2, and 4 mM, respectively. Addition of 2 mM lecithin to 2 mM TDCA, 4 mM TCDCA, or 5 mM TCA reduced or eliminated membrane leakage and lowered the IMMC. For TDCA and TCDCA, the protective effect of vesicles was entirely attributable to reduction in IMMC; in contrast for TCA, the protective effect exceeded that which would have been expected based solely on reduction of the IMMC. Inclusion of cholesterol attenuated the binding of bile salts to vesicles and raised the IMMC, thereby reducing the protective effect of lecithin over the time course of these studies. Although there was loss of phospholipid and cholesterol from the erythrocyte membranes on addition of bile acids even in the presence of vesicles, the ratio of cholesterol to phospholipid in the erythrocyte membrane did not change. CONCLUSION: Lecithin protects against membrane disruption by hydrophobic bile salts by lowering the IMMC. Cholesterol added to lecithin raises the bile salt IMMC and reduces or eliminates this protective effect. This mechanism of potentiation of bile salt toxicity by cholesterol may be an important contributor to the pathogenesis of gallbladder disease in cholesterol cholelithiasis.

Bile↗
PubMed1996

Total parenteral nutrition impairs bile flow and alters bile composition in newborn piglet.

Cholestatic liver disease complicates total parenteral nutrition (TPN) in premature neonates. We investigated TPN-induced liver disease in the newborn piglet, hypothesizing that: (1) TPN impairs bile flow by reducing the bile acid-dependent (BADF) and the bile acid-independent component of bile flow (BAIF); and (2) TPN changes bile composition. For three weeks, eight piglets received TPN and nine piglets were fed milk. Basal bile flow was measured and bile composition analyzed for bile acids, cholesterol (C), phospholipids (PL), and PL fatty acids. Bile flow was also measured after stimulation with 20, 50, and 100 mu/kg taurocholic acid (TCA). Liver histology and bilirubin content were examined. Basal bile flow was reduced from 11.6 +/- 1.2 microliters/g liver/10 min in orally fed animals to 1.6 +/- 0.4 microliters/g liver/10 min in the TPN group. The stimulated bile flow in the TPN group did not respond to TCA and was lower than in the orally fed animals at each TCA dose. Both BADF and BAIF were significantly lower in the TPN group. Bile acid secretion was less than 50% of control values and total C and PL secretions were less than 5% of control. Liver and serum bilirubin were elevated in the TPN group. The newborn piglet is a valid model to study TPN-induced cholestasis, characterized by decreased bile acid secretion, impaired BADF and BAIF, and reduced bile flow stimulation after intravenous TCA.

Animals↗