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PubMed2003

Unique inhibition of bile salt-induced apoptosis by lecithins and cytoprotective bile salts in immortalized mouse cholangiocytes.

Bile duct epithelium is physiologically exposed to high concentrations of bile salts, suggesting the presence of a cytoprotective mechanism(s). The aim of this study was to clarify whether bile salts cause bile duct cell damage and to elucidate the mechanism(s) providing protection against such an action of bile salts. Immortalized mouse cholangiocytes were incubated with taurocholate, taurochenodeoxycholate, glycochenodeoxycholate (GCDC), taurodeoxycholate, and tauroursodeoxycholate (TUDC), followed by flow-cytometric analysis and caspase activity assay to evaluate the induction of apoptosis. GCDC time-dependently induced caspase 3 (3.4-fold)- and caspase 9 (1.4-fold)-mediated apoptosis of cholangiocytes, but this was inhibited by lecithins and TUDC. Further, expression of cholangiocyte bile salt transporters (apical sodium-dependent bile salt transporter [Asbt] and multidrug resistance protein 3 [Mrp3]) was examined by RT-PCR and western blotting, and cholangiocyte bile salt uptake was determined using radiolabeled bile salts. Expression of cholangiocyte Asbt and Mrp3 was increased by bile salts, whereas lecithins interestingly reduced bile salt uptake to inhibit cholangiocyte apoptosis. In conclusion, bile salts themselves cause cholangiocyte apoptosis when absorbed by and retained inside the cell, but this is inhibited by washing out cytotoxic bile salts according to Mrp3, a rescue exporting molecule. Biliary lecithin is seemingly another cytoprotective player against cytotoxic bile salts, reducing their uptake, and this is associated with a reduced expression of Mrp3.

Animals↗
PubMed1976

Bilirubin conjugates in bile of man, rat and dog. Semi-quantitative analysis of bile composition by thin-layer chromatography.

1. Conjugated bile pigments, separated in two fractions by semi-quantitative t.l.c. performed on silicic acid with phenol/water as the developing solvent, were treated with diazotized ethyl anthranilate. Resulting dipyrrylazo derivatives were analysed by quantitative t.l.c. 2. The tentative structure elucidation of tetrapyrrolic bilirubin conjugates and semi-quantitative evaluation of rat bile, post-obstructive human bile and dog bile composition is presented. 3. Homogeneous and mixed hexuronic acid diesters of bilirubin containing glucuronic acid constitute 51% of the total conjugates in normal rat bile, 45% of those in human post-obstructive bile and 38% of those in obstructed rat biles. 4. Monoconjugated bilirubin amounts to 33% of total conjugated bile pigments in normal rat bile, and 17 and 14% in post-obstructive hepatic human bile and gall-bladder bile of dog respectively. After loading with unconjugated bilirubin a greater amount of monoconjugates (56%) occur in the rat bile, whereas bilirubin diglucuronide excretion is decreased (34%). 5. In gall-bladder bile of normal dog, 40% of glucose-containing diconjugates, 32% of homogeneous and/or mixed hexuronic acid (mainly glucuronic acid) diesters of bilirubin and 14% of xylose-containing diconjugates are estimated. 6. Increased amounts of bilirubin conjugates, including some with unidentified uronic acid groups, were observed in cholestatic rat biles and quantities of conjugates with glucuronic acid were decreased.

Animals↗
PubMed1984

The biliary excretion of sulphated and non-sulphated bile acids and bilirubin in patients with external bile drainage.

The biliary excretion of total bilirubin and bile acids, and the fate of tracer doses of radioactive sulphated and non-sulphated bile acids, were studied in patients with percutaneous transhepatic bile drainage. Non-sulphated bile acids were excreted in bile early after biliary decompression, and the serum total 3 alpha-hydroxy bile acid concentrations fell rapidly to normal. Biliary bilirubin excretion was both less than and delayed compared with that of bile acids, and the serum bilirubin concentration fell more slowly. The serum disappearance of [3H]chenodeoxycholate-3-sulphate was slower than that of [14C]glycocholate in all patients with bile drainage, the difference being more marked in the jaundiced patients. The radioactive sulphated bile acids were recovered predominantly in the urine of the jaundiced patients. In contrast [14C]glycocholate was excreted almost exclusively in bile. In an anicteric patient, radioactive sulphated bile acid disappeared from the serum more quickly, and biliary recovery exceeded that in the urine. The studies demonstrate the differences in handling of total bilirubin, and sulphated and non-sulphated bile acids in man after the relief of bile duct obstruction. The biliary excretion of radioactive labelled sulphated bile acids is low for at least 1 week after biliary drainage, but later becomes the predominant route for excretion in the anicteric patient.

Aged↗
PubMed1987

Determinants of bile formation during development: ontogeny of hepatic bile acid metabolism and transport.

The studies cited in this brief review stress that the development of hepatic transport processes is extraordinarily complex. Important changes in hepatic morphology and synthetic capacity are required before maturation of membrane carriers for bile acids. Transport systems at both poles of the hepatocyte develop independently. An increase in bile acid synthesis at several stages during the development appears to be an ontogenic event that is programmed to occur in concert with functional maturation of the enterohepatic circulation. Expression of specific membrane transporters for bile acids can be observed in fetal liver and postnatal ileum during periods of expansion of the bile acid pool. It is likely that specific defects, such as congenitally absent or defective bile acid transport proteins, will eventually be discovered in rare patients with undefined cholestatic syndromes. The absence of active ileal bile acid transport has recently been demonstrated in several children with congenital bile acid malabsorption. Whether bile acids can actually induce or regulate production of their own carriers during development has not been determined, but an increase in bile acid pool through feeding of exogenous bile acid has been shown to stimulate an increase in plasma membrane carriers for bile acids in adult rat liver. Thus, a number of factors, including available driving forces for transport, bile acid pool size and composition, effectiveness of intracellular compartmentation and transfer, and the function of membrane carriers, can all contribute to low rates of bile flow and bile acid secretion, depending on the stage of development.

Animals↗
PubMed1985

Hepatic transport of bile salt and bile composition following total parenteral nutrition with and without lipid emulsion in the rat.

The effect of total parenteral nutrition (TPN) on bile flow and composition and on hepatic bile acid transport maximum (Tm) and bile salt-independent bile flow (BSIF) was studied in the rat following seven days TPN containing 33% calories from Intralipid (IL) or Liposyn (LP) or 0% calories from lipid. All TPN regimes markedly reduced bile flow. In no case did TPN cause an increase in bile cholesterol concentration or saturation relative to bile acid and phospholipid. Bile acid Tm was reduced in rats receiving either 0% lipid or 33% IL; BSIF was reduced only in the 0% lipid group. Rats receiving 33% LP had a higher bile flow than the other TPN regimes while bile acid Tm and BSIF were similar to controls. It is proposed that in established TPN, bile flow is reduced largely as a result of decreased hepatic bile acid excretion. In the rat, TPN has no deleterious effect on the molar concentration of cholesterol, phospholipid or bile acid in bile secreted by the hepatocyte. The significant differences between the effect of the two lipid emulsions on hepatobiliary function require further study.

Animals↗
PubMed1984

Fecal and biliary bile acid patterns in children with bile acid malabsorption.

Bile acid metabolism was examined in two children with bile acid malabsorption, who were being treated with intravenous hyperalimentation. Fecal bile acid excretion was 1,261 mumol/m2/day in a child with bile acid malabsorption of unknown origin, and 1,877 mumol/m2/day in a child with secondary bile acid malabsorption after an operation for long-segment aganglionosis. These values were approximately 10 times higher than those in diarrheal or nondiarrheal children without apparent abnormalities in bile acid metabolism. Fecal bile acids in these patients with bile acid malabsorption were almost completely conjugated, with little unconjugated bile acid present. It is possible that the disturbed bile acid deconjugation in the intestine might be caused by a rapid intestinal transit time, which was found in our patients with bile acid malabsorption. In the analysis of biliary lipid composition, children with bile acid malabsorption were shown to have a chenodeoxycholate-dominant pattern, an increased glycine- to taurine-conjugated bile acid ratio, and markedly supersaturated cholesterol. Such profiles may be related not only to bile acid malabsorption but also to cholestasis, presumably due to intravenous hyperalimentation.

Bile↗
PubMed2000

Bile acids in porcine fetal bile.

A study of the biliary bile acid composition in porcine fetus compared with that of the adult pig is described. Biles, collected during gestation (weeks 4, 15 to 17 and at birth), aged six months and two years old, were analyzed by gas-liquid chromatography and capillary GC-MS. Bile acids were separated into different conjugate groups by chromatography on the lipophilic anion exchange gel, piperidinohydroxypropyl Sephadex LH-20. All and one fourth of the total bile acids in the bile of weeks 4 and 15 of gestation, respectively, were present as unconjugated form, however, only a trace of unconjugated bile acids was present in bile of late gestation, the young and the adult pigs. The ratio of glycine/taurine (G/T) conjugates in the conjugated fraction of the fetal bile at 15 weeks gestation was less than 1, which markedly contrasted with the conjugation pattern for adult bile where the ratio of G/T conjugates was approximately more than 9. The predominant acids identified in porcine fetal bile of the 4 weeks gestation were cholic acid (3alpha,7alpha,12alpha-trihydroxy-5beta-chola n-24-oic acid) and chenodeoxycholic acid (3alpha,7alpha -dihydroxy-5beta-cholan-24-oic acid). However, cholic acid in late gestation, young, and adult bile was the smallest component, whereas chenodeoxycholic acid was still the major constituent of these biles. The presence of small but valuable amounts of allocholic acid (3alpha,7alpha,12alpha-trihydroxy-5alpha-chol an-24-oic acid) and cholic acid in early gestation suggested the presence of 12alpha-hydroxylase activity of steroid nucleus in fetal liver. Considerable amounts of glycine-conjugated hyodeoxycholic acid were found in the bile of the gestation periods, suggesting the placental transfer of this bile acid from maternal circulation.

Aging↗
PubMed1975

Bile acid pattern of gallbladder and hepatic bile in patients with and without cholesterol gallstones.

Bile acid composition of hepatic and gallbladder bile was examined in a group of 18 patients with uncomplicated cholelithiasis and a control group consisting of 13 patients with healed duodenal ulcers. Bile specimens were taken during laparotomy. Molar concentrations of the different bile acids in hepatic and gallbladder bile were determined. The ratios between the molar concentrations of the different bile acids were calculated. In order to compare these molar ratios in hepatic and gallbladder bile the quotients between identical molar ratios of hepatic and gallbladder bile were calculated in each subject. Bile acid concentration of the gallbladder bile was found to be lower in the gallstone patients. Trihydroxy or dihydroxy bile acid molar ratio was lower in the gallstone group. Hepatic to gallbladder relative trihydroxy to dihydroxy and cholate to deoxycholate bile acid ratios were elevated in the gallstone patients. This might indicate that an increased formation of deoxycholate is the main cause for the decreased trihydroxy to dihydroxy bile acid molar ratio observed in the gallbladder bile of patients with cholesterol gallstones.

Adult↗
PubMed1992

Separation of bile vesicles and micelles by gel filtration chromatography: the importance of the intermicellar bile salt concentration.

Micelles and vesicles coexist in native bile. Mixed micelles are composed of bile salt, phospholipid, and cholesterol. Micellar bile salt is in equilibrium with the aqueous phase bile salt (intermicellar bile salt), and mixed micelles can be converted to cholesterol-phospholipid vesicles by depletion of bile salt. To determine the amount of cholesterol carried in vesicles and micelles, these two populations must be separated without altering the relative proportion of each. Based on the size difference between micelles and vesicles, gel filtration chromatography has been used to accomplish this separation. We reasoned that to maintain the proportion of micelles and vesicles in bile, the column must be equilibrated and eluted with buffer containing the intermicellar bile salt concentration (IMBC) and species. To test this hypothesis we created a model bile composed exclusively of micelles, a solution containing micelles and vesicles, and a model bile containing all vesicles, as demonstrated by quasielastic light scattering. Gel filtration on Sepharose 4B demonstrated that model vesicles and micelles could be separated on a column eluted with buffer containing bile salt at the IMBC. However, a modest decrease in the buffer bile salt concentration (less than 1 mmol/L) resulted in complete conversion of micelles to vesicles. A comparable increase in the buffer bile salt concentration converted vesicles to micelles. Using only taurocholate in the eluting buffer at the IMBC caused a complete shift of micelles to vesicles, whereas using only taurochenodeoxycholate resulted in conversion of vesicles to micelles. An initial collection of rat bile separated on a column equilibrated with the measured IMBC demonstrated that 94% of the cholesterol was in the micellar fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Role of ductular bile water reabsorption in canine bile secretion.

To quantitate ductular and/or ductal bile water reabsorption and to define its role in hepatic bile formation, spontaneous and taurocholate-stimulated bile flow and composition were measured in anesthetized dogs postprandially (n = 4) and after a 24-hour (n = 4) and a 48-hour (n = 4) fasting period. Spontaneous bile flow in fed dogs (0.344 +/- 0.116 microliter/min/gm liver tissue) was significantly higher than that in 24-hour (0.179 +/- 0.046 microliter/min/gm) and 48-hour fasted animals (0.096 +/- 0.085 microliter/min/gm). One 48-hour fasted dog was virtually cholestatic (spontaneous bile flow 0.004 microliter/min/gm), and another 48-hour fasted animal had a mean bile flow rate as low as 0.036 microliter/min/gm. Calculated ductular bile water reabsorption (carbon 14-erythritol biliary clearance minus bile flow) was the same in the three groups of animals (0.166 +/- 0.056, 0.208 +/- 0.033, and 0.204 +/- 0.055 microliter/min/gm, respectively). Administration of sodium taurocholate (0.5 to 2.0 mumol/min/kg) revealed intact canalicular secretory capacity in all dogs, and no change in bile water reabsorption rate was observed during choleresis. Bile chloride and bicarbonate concentrations during spontaneous secretion were significantly lower in 48-hour fasted dogs when compared with fed animals. In the two 48-hour fasted dogs with a very low rate of spontaneous bile flow, chloride and bicarbonate concentrations in hepatic bile were as low as those seen in gallbladder bile (5 to 10 mEq/L) and increased during taurocholate choleresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1982

Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum.

This investigation was undertaken in order to (a) characterize the postprandial inflow of individual bile acids to the liver and (b) determine if peripheral venous bile acid levels always adequately reflect the portal venous concentration, or if saturation of hepatic bile acid uptake can occur under physiological conditions. In five patients with uncomplicated cholesterol gallstone disease, the umbilical cord was cannulated during cholecystectomy, and a catheter was left in the left portal branch for 5 to 7 d. The serum concentrations of cholic acid, chenodeoxycholic acid, and deoxycholic acid in portal venous and systemic circulation were then determined at intervals of 15 to 30 min before and after a standardized meal. A highly accurate and specific gas chromatographic/mass spectrometric technique was used. The sum of the fasting concentrations of the three bile acids averaged 14.04+/-4.13 mumol/liter in portal venous serum, and 2.44+/-0.31 mumol/liter in peripheral venous serum. The estimated hepatic fractional uptake of cholic acid was approximately 90%, and those of chenodeoxycholic acid and deoxycholic acid were 70-80%. This resulted in an enrichment of systemic bile acids in the dihydroxy bile acid species. In response to a standardized meal, portal venous bile acid concentrations increased two- to sixfold, with a peak seen 15-60 min after the meal. The maximum postprandial portal venous bile acid concentration averaged 43.04+/-6.12 mumol/liter, and the corresponding concentration in peripheral serum was 5.22+/-0.74 mumol/liter. The estimated fractional uptakes of the individual bile acids were not affected by the increased inflow to the liver. The peripheral venous concentrations of individual as well as total bile acids were well correlated with those in portal venous serum. The results (a) give a quantitation of postprandial bile acid inflow to the liver and (b) indicate that the hepatic uptake system for bile acids in healthy man cannot be saturated during maximal inflow of endogenous bile acids. Measurement of peripheral serum bile acids can thus give important information on the status of the enterohepatic circulation.

Aged↗
PubMed1994

Bile salt-dependent and bile salt-independent cholesteryl ester hydrolase activities in rat liver cytosol.

These studies report on the relationship between the bile salt-dependent and -independent cholesteryl ester hydrolase (CEH) activities found in rat liver cytosol. The two activities show very similar Michaelis-Menten substrate kinetics and pH dependence. After gel filtration of cytosol, the bile salt-independent activity elutes much earlier than the bile salt-dependent activity, suggesting that the two activities are associated with entities of different molecular size. However, when gel filtration is carried out in the presence of bile salt, the bile salt-dependent activity elutes as a large aggregate, similar to the bile salt-independent activity's behavior in the absence of bile salt. Both activities coelute after cytosol is passed through an ion exchange column. After each chromatographic procedure the recovery of the bile salt-dependent activity was substantially higher than the recovery of the bile salt-independent activity. When cytosol is incubated with anti-rat pancreatic CEH in the absence of cholate, the bile salt-dependent activity is inhibited more than 90% whereas bile salt-independent activity remains unaffected even at high antibody concentrations. When cytosol is incubated with anti-rat pancreatic CEH in the presence of cholate both CEH activities remain unaffected. The prevention of immunoinhibition by cholate seems to be specific for this detergent since CHAPS, a cholate analog, does not prevent immunoinhibition of the bile salt-dependent activity by anti-CEH. The experimental results are consistent with a model for CEH activity in liver cytosol in which there is only one enzyme that can exist in a monomeric, inactive form (that can be activated by addition of cholate to the assay and represents the bile salt-dependent activity) and in an active complex comprising several enzyme monomers as well as cholate micelles (that accounts for the bile salt-independent activity).

Animals↗
PubMed2000

Subcellular organization of bile acid amidation in human liver: a key issue in regulating the biosynthesis of bile salts.

To extend our knowledge of how the synthesis of free bile acids and bile salts is regulated within the hepatocyte, bile acid-CoA:amino acid N-acyltransferase and bile acid-CoA thioesterase activities were measured in subcellular fractions of human liver homogenates. Some bile acids, both conjugated and unconjugated, have been reported to be natural ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. The conversion of [(14)C]choloyl-CoA and [(14)C]chenodeoxycholoyl-CoA into the corresponding tauro- and glyco-bile acids or the free bile acids was measured after high-pressure liquid radiochromatography. There was an enrichment of the N-acyltransferase in the cytosolic and the peroxisomal fraction. Bile acid-CoA thioesterase activities were enriched in the cytosolic, peroxisomal, and mitochondrial fractions. The highest amidation activities of both choloyl-CoA and chenodeoxycholoyl-CoA were found in the peroxisomal fraction (15-58 nmol/mg protein/min). The K(m) was higher for glycine than taurine both in cytosol and the peroxisomal fraction.These results show that the peroxisomal de novo synthesis of bile acids is rate limiting for peroxisomal amidation, and the microsomal bile acid-CoA synthetase is rate limiting for the cytosolic amidation. The peroxisomal location may explain the predominance of glyco-bile acids in human bile. Both a cytosolic and a peroxisomal bile acid-CoA thioesterase may influence the intracellular levels of free and conjugated bile acids.

Acyltransferases↗
PubMedDate not supplied

The cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids in intestinal cell lines IEC-6 and Caco-2.

Bile acids, especially those with hydrophobic properties, are known to possess cytotoxicity. However, the mechanisms responsible for the cytotoxicity of bile acids are still under investigation. On the other hand, the hydrophilic bile acid, ursodeoxycholic acid has been reported to exhibit therapeutic effects against cytotoxic hydrophobic bile acids. The aim of the present study was to investigate the cytotoxicity of individual bile acids and combinations of bile acids using the intestinal cell lines IEC-6 and Caco-2 cells. The cytotoxicities of individual bile acids and the effects of various bile acid combinations were evaluated using the MTS [3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. The bile acids induced cytotoxic effects depending on their hydrophobicity except for hyodeoxycholic acid. In the study for the effects of combined bile acids, not only ursodeoxycholic acid but other hydrophilic bile salts such as cholic acid and hyocholic acid exhibited cytoprotection against deoxycholic acid-induced cytotoxicity. Moreover, even some hydrophobic bile acids, such as chenodeoxycholic acid also exhibited cytoprotection. It is possible that the cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids under certain conditions. The understanding of the precise mechanism of this phenomenon remains to be determined.

Bile Acids and Salts↗
PubMed1995

Regulation of bile acid synthesis in the rat: relationship between hepatic cholesterol 7 alpha-hydroxylase activity and portal bile acids.

Bile acid biosynthesis has been believed to be regulated by negative feedback control; however, recent experiments have cast considerable doubts on the concept. The aim of the study was to examine the consensus of the negative feedback regulation of bile acids by clarifying the correlation between the portal bile acids and the rate-limiting enzyme of bile acid biosynthesis, hepatic microsomal cholesterol 7 alpha-hydroxylase. We measured the enzyme activity and the portal bile acids in male Wistar rats that were orally administered three different bile acids or cholestyramine for 2 weeks. The serum level of 7 alpha-hydroxycholesterol was also determined to verify whether it would be a parameter of bile acid synthesis rate in the rat. The activity of cholesterol 7 alpha-hydroxylase increased about threefold in rats treated with cholestyramine when compared with controls. On the other hand, in rats fed ursodeoxycholic, chenodeoxycholic, and deoxycholic acids, the enzyme activities decreased to 40%, 26%, and 28%, respectively. Treatment with cholestyramine had no significant effect on the portal bile acid concentration. Administration of ursodeoxycholic and chenodeoxycholic acids resulted in a significant increase in the concentration of portal bile acids, whereas deoxycholic acid feeding did not significantly affect it. In the control group, conjugated cholic acid constituted a major part of the portal bile acids while the administered bile acid and its metabolites became predominant in each bile acid feeding group. Treatment with ursodeoxycholic acid made the portal bile acids more hydrophilic, but, by contrast, administration of chenodeoxycholic, deoxycholic acids, and cholestyramine made the portal bile acids more hydrophobic.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2005

Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice.

BACKGROUND/AIMS: Bile flow consists of bile salt-dependent bile flow (BSDF), generated by canalicular secretion of bile salts, and bile salt-independent flow (BSIF), probably of combined canalicular and ductular origin. Bile salt transport proteins have been identified in cholangiocytes, suggesting a role in control of BSDF and/or in control of bile salt synthesis through cholehepatic shunting. METHODS: We studied effects of bile duct proliferation under non-cholestatic conditions in multidrug resistance-2 P-glycoprotein (Abcb4)-deficient multidrug resistance gene-2 (Mdr2(-/-)) mice. BSDF and BSIF were determined in wild-type and Mdr2(-/-) mice during infusion of step-wise increasing dosages of tauroursodeoxycholate (TUDC). Cholate synthesis rate was determined by 2H4-cholate dilution. Results were related to expression of transport proteins in liver and intestine. RESULTS: During TUDC infusion, BSDF was increased by approximately 50% and BSIF by approximately 100% in Mdr2(-/-) mice compared with controls. Cholate synthesis rate was unaffected in Mdr2(-/-) mice. Hepatic expression of the apical sodium-dependent bile salt transporter (Asbt), its truncated form (tAsbt) and the multidrug resistance-related protein 3 were upregulated in Mdr2(-/-) mice. CONCLUSIONS: Bile duct proliferation in Mdr2(-/-) mice enhances cholehepatic shunting of bile salts, which is associated with a disproportionally high bile flow but does not affect bile salt synthesis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1994

Effect of taurohyodeoxycholic acid, a hydrophilic bile salt, on bile salt and biliary lipid secretion in the rat.

Taurohyodeoxycholic acid is a natural 6 alpha-hydroxylated bile acid with an apparent hydrophilicity intermediate between those of tauroursodeoxycholic and taurocholic acids. We investigated in the rat the hepatobiliary metabolism, choleretic properties, and biliary maximum secretory rate (SRmax) of taurohyodeoxycholic in comparison with these two bile salts. Each compound was infused intravenously, at a rate increased in a stepwise manner from 100 to 300 nmol/min/100 g body wt, in bile salt-depleted bile fistula rats. The three bile salts appeared rapidly starting with the infusion and increased to represent more than 95% of the total bile salts. No apparent biliary metabolites were formed. All the bile salts caused a dose-dependent increase in bile flow and biliary lipid output. The absolute increase in bile flow was lower in rats infused with taurohyodeoxycholic acid, yet the volume of bile formed per nanomole of secreted bile salt was 13.8 nl for taurohyodeoxycholic, 6.4 nl for tauroursodeoxycholic acid, and 10.9 nl for taurocholic. The SRmax values were 1080, 3240, and 960 nmol/min/100 g, respectively. At all infusion rates, taurohyodeoxycholic acid caused a greater (P < 0.001) secretion of biliary lecithin compared to the other bile salts. There were no significant differences in the biliary secretion of cholesterol and proteins. Electron microscopy showed the recruitment of vesicles and lamellar bodies around and within bile canaliculi. In conclusion, taurohyodeoxycholic promotes a biliary lecithin secretion greater than expected from physicochemical predictions, representing a novel secretory property with potential pharmacological relevance.

Animals↗
PubMed2004

Partial characterization of cytoprotective mechanisms of lecithin against bile salt-induced bile duct damage.

BACKGROUND: We recently demonstrated that cyclosporine A causes a disproportionate reduction of biliary lipid secretion, and this is inhibited by hydrophilic bile salts through the enhancing of biliary lecithin secretion. In the present study, the underlying mechanism of such a cytoprotective action of hydrophilic bile salts was determined with attention to the possible role of lecithin. METHODS: Immortalized mouse cholangiocytes were cultured for 4 h with taurine conjugates of a hydrophobic bile salt (cholate [TC]), and hydrophilic bile salts (ursodeoxycholate [TUDC], betamuricholate [TbetaMC], and alphamuricholate [TalphaMC]), at 200 microM, in the presence or absence of lecithin (5, 10, 25, 50, 100, or 200 microM), followed by flow cytometric detection of apoptosis, using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cholangiocyte bile salt transporter mRNAs (apical sodium-dependent bile-salt transporter [Asbt] and multidrug resistance protein 3 [Mrp3]) were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Apoptosis was induced by all of the bile salts (TC > TUDC, TbetaMC, and TalphaMC). Interestingly, bile salt-induced apoptosis was inhibited by lecithin in a concentration-dependent manner. Further, RT-PCR showed that the expressions of Asbt and Mrp3 mRNAs were enhanced by all the bile salts, whereas lecithin reduced Asbt expression, but enhanced Mrp3 expression. CONCLUSIONS: These findings indicate that bile salts cause bile-duct cell damage through Asbt-mediated uptake, but that biliary lecithin physiologically inhibits such damage by reducing the expression of this transporter. In addition, the induction of Mrp3 expression by lecithin may play a role in inhibiting the accumulation of bile. Thus, the modulation of lecithin secretion into bile may be another important target for the treatment of biliary disorders.

Animals↗