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Objetive: To evaluate the enterohepatic circulation of 75-Selenium turoselecolic acid ( 75 Se-SeHCAT) during the first 3 h and its correlation with the abdominal retention at the 7th day (AR 7 ), as contribution to the clinical study of biliar acid malabsorption (BAM)., Materials and Methods: 38 patients with chronic diarrhea were retrospectively studied. Acquisition protocol included static abdominal images at 1st, 2nd and 3rd hour and the 7th day after oral administration of the radiopharmaceutical. Images of 1-3 h determined 5 patterns of enterohepatic circulation that, due to their location, were characterized as: 1) gallbladder 2-3 h, 2) gallbladder 3 h, 3) gallbladder-abdomen 2-3 h, 4) abdomen, 5) upper left abdomen. The association of these patterns with the AR 7 (Fisher, STATA) were investigated. Patients were classified as Non BAM (AR 7  > 15%), mild-BAM (AR 7 15-10%), moderate-BAM (AR 7 10-5%) or severe-BAM (AR 7  < 5%)., Results: 19 patients had an AR 7 diagnostic of BAM (7 mild-BAM, 5 moderate-BAM, 7 severe-BAM). The pattern "gallbladder at 2-3 h" was statistically associated with Non BAM (p 0,008), while "gallbladder-abdomen at 2-3 h" was correlated with having BAM (p 0,029)., Conclusion: Variations detected at the abdominal level in images during the first 3 h were associated with changes in intestinal absorption and the incorporation of the radiopharmaceutical into the pool of bile acids, so visual interpretation of the images at 2nd and 3rd hour could be useful in the final assessment of the study., (Copyright © 2021 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Background: 23-seleno-25-homo-tauro-cholic acid (SeHCAT) scanning to rule out bile acid diarrhea (BAD) in patients with chronic diarrhea has a high yield. Our previous study showed that patients with terminal ileal (TI) Crohn's disease, TI resection, or cholecystectomy were highly likely to have an abnormal scan. As a result, we encouraged clinicians to use a therapeutic trial of a bile acid sequestrant in these patients, instead of scanning. This may have reduced diagnostic yield of the test, so we examined this issue, as well as factors predicting an abnormal scan, in a large cohort of patients referred subsequently., Methods: We retrospectively identified 1,071 consecutive patients with chronic diarrhea undergoing SeHCAT scanning at Leeds Teaching Hospitals Trust from 2012 to 2016. We reviewed electronic patient records to obtain information on presenting gastrointestinal symptoms and any proposed risk factors for BAD. BAD was categorized according to subtype and severity., Key Results: As expected, indications for scanning changed between 2012 and 2016, with a significant reduction in referrals with TI Crohn's disease or resection year-on-year (P < 0.001). Despite this, 457 (42.7%) patients had BAD and there was no downward trend in yield of SeHCAT during the 5 year period (P = 0.39). Overall, 51.6% had type II BAD, 36.1% type III, and 12.3% type I. BAD was mild in 31.7%, moderate in 34.4%, and severe in 33.9%. In total, 653 (61.0%) patients had no known risk factors, other than chronic diarrhea, but 233 (35.7%) of these individuals had BAD, and in 143 (61.4%), this was moderate or severe., Conclusions and Inferences: Despite reduced referrals for SeHCAT scanning in those with clear risk factors for BAD, the yield remained > 40%. One-third of those without known risk factors had BAD., (© 2019 John Wiley & Sons Ltd.)

The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA-induced gut hormones, fibroblast growth factor 19 and glucagon-like peptide 1, and the BA transport systems, apical sodium-dependent bile acid transporter and Na + -taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393-1404)., (© 2016 by the American Association for the Study of Liver Diseases.)

Objective: Bile-acid diarrhoea (BAD) is a recognized cause of chronic diarrhoea; however, its detection remains suboptimal. Currently, there is a paucity of follow-up studies evaluating BAD. This work evaluates the natural history of BAD by examining individuals diagnosed with BAD [7 days of Se-homocholic acid taurine (SeHCAT) retention<10%] and determining the use of and response to bile-acid sequestrants (BAS)., Materials and Methods: Of the 515 patients, 40% (207/515) who underwent an SeHCAT test at Sheffield Teaching Hospitals (2001-2012) for chronic diarrhoea had BAD. Of the 207 (51%) patients, 107 were diagnosed between 2001 and 2009. In accordance with the guidelines, all of these patients were commenced on BAS. In March 2013, these individuals were reassessed either in the clinic or over the telephone as part of a local service evaluation project. Comparisons were made of both pretreatment and post-treatment variables using a Wilcoxon rank test., Results: Of the 107 patients, 54% (58/107) were followed up, with a median time since diagnosis of 6 years. Among them, 38% were still using BAS at follow-up, with 28% using alternative antidiarrhoeals. The median stool frequency decreased from seven stools per day to three (P=0.0008) in those using BAS. The 34% of patients not receiving treatment had no change in their daily bowel frequency. The main reason for discontinuing treatment was poor tolerability of the BAS (colestyramine/colestipol)., Conclusion: Our findings indicate that BAD is a chronic condition that best improves with BAS. Consideration should be given to therapeutic options that have a better tolerability profile.

There have been numerous reports that infusion of either natural bile or bile salts into the duodenum evokes a rapid increase in pancreatic secretion through the release of the hormone secretin from the duodenal mucosa. We have extended this observation by the demonstration of an additional late increase in secretion which persisted for many hours and have sought to identify the processes underlying this increase. In anaesthetised rats, infusion of 20 mM taurocholate into the duodenum caused a staircase-like increase in the weight of pancreatic secretion which extended over many hours during which, the HCO[Formula: see text] and protein output of the secretion showed only minimal changes. This effect was also reproduced with intra-duodenal infusion of natural bile which was inferred to act though its taurocholate content. Since the stimulatory action was also obtained with superfusion of taurocholate or natural bile onto the small intestine and by intravenous injection of taurocholate, it was concluded that taurocholate acted by being absorbed into the bloodstream and then by exerting a stimulatory action on the exocrine pancreas. This action was inhibited by puromycin (a protein synthesis inhibitor), by furosemide (a Na( + )/K( + )/2Cl(-) cotransporter inhibitor), though not by SITS (an inhibitor of Cl(-)/HCO[Formula: see text] exchange). The long lasting increase in pancreatic serous secretion would be consistent with the possible activation of gene transcription by taurocholate leading to increased activity of the Na( + )/K( + )/2Cl(-) cotransporter through which the acinar cells increased their secretions.

Oral delivery of protein or polypeptide drugs remains a challenge due to gastric and enzymatic degradation as well as poor permeation across the intestinal epithelia. In this study, liposomes containing bile salts were developed as a new oral insulin delivery system. The primary goal was to investigate the effect of cholate type, particle size and dosage of the liposomes on the hypoglycemic activity and oral bioavailability. Liposomes containing sodium glycocholate (SGC), sodium taurocholate (STC) or sodium deoxycholate (SDC) were prepared by a reversed-phase evaporation method. After oral administration, all liposomes elicited a certain degree of hypoglycemic effect in parallel with an increase in blood insulin level. The highest oral bioavailability of approximately 8.5% and 11.0% could be observed with subcutaneous insulin as reference for SGC-liposomes in non-diabetic and diabetic rats, respectively. Insulin-loaded liposomes showed slower and sustained action over a period of over 20 h with peak time around 8-12h. SGC-liposomes showed higher oral bioavailability than liposomes containing STC or SDC and conventional liposomes. The hypoglycemic effect was size-dependent with the highest at 150 nm or 400 nm and was proportionally correlated to the administered dose. The results supported the hypothesis of insulin absorption as intact liposomes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cholesterol 7alpha-hydroxylase (CYP7A1) is regulated by bile acids through the farnesoid X receptor (FXR) mechanism in a negative feedback fashion. However, the fact that CYP7A1 is down-regulated by intraduodenal administration of bile acid, but not by intravenous administration may not be explained only by this mechanism. The aim of this study was to establish a new rat model with reconstructed or simulated enterohepatic circulation to examine if intravenous or portal administration of bile acid can regulate CYP7A1. Under biliary drainage, taurocholate (0 or 6 micromol/h/100g body weight) was administered continuously for 48h into the duodenum (ID-0/ID-6), femoral vein (IV-0/IV-6), or portal vein (IP-0/IP-6) to create a condition in which biliary bile acids were continuously lost, and a similar dose of taurocholate was supplied to the liver simultaneously. CYP7A1 activity and mRNA expression of the ID-0 group were significantly increased compared with the no treatment (NT) group. CYP7A1 activity and mRNA expression of the ID-6 group were suppressed significantly to 41 and 46% of those of the ID-0 group, respectively. In the IV-6 and IP-6 groups, however, enzyme activity and mRNA expression were decreased slightly, but the suppression was not statistically significant. The results suggested that portal as well as intravenous administration of bile acids cannot suppress bile acid synthesis as effectively as intraduodenal administration. It was concluded that an unidentified regulatory factor other than the nuclear receptors may be involved in bile acid synthesis in vivo.

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.

Bile salts (BS) have been shown to suppress the secretion of very-low-density lipoprotein-triglyceride (VLDL-TG) in rat and human hepatocytes in vitro. In the present study, we investigated whether the transhepatic BS flux affects VLDL-TG concentration and hepatic VLDL-TG secretion in vivo. In rats, the transhepatic BS flux was quantitatively manipulated by 1-week chronic bile diversion (BD), followed by intraduodenal infusion with taurocholate (TC) or saline for 6 h. In mice, the transhepatic BS flux was manipulated by a 3-week dietary supplementation with TC (0.5 wt.%) or cholestyramine (2 wt.%). In rats, BD followed by saline or TC infusion did not affect plasma triacylglycerol (TG) concentration, hepatic TG production rate or VLDL lipid composition, compared to control rats. In mice supplemented for 3 weeks with TC or cholestyramine, the transhepatic BS flux was increased by 335% and decreased by 48%, respectively, compared to controls. Among the three experimental groups of mice, an inverse relationship between transhepatic BS flux and either plasma TG concentration (R(2)=0.89) or VLDL-TG production rate (R(2)=0.87) was observed, but differences were relatively small. Present data support the concept that BS can reduce VLDL-TG concentration and inhibit hepatic TG secretion in vivo; however, this occurs only at supraphysiological transhepatic BS fluxes in mice.

In the rat, the ob gene product, leptin, putatively regulates energy balance via appetite control and energy expenditure. Bile acids in the intestinal lumen are necessary for efficient absorption of dietary lipids and may trigger the release of regulatory peptides. To investigate whether bile acids play a role in leptin gene expression, we altered the bile acid pool and then measured leptin mRNA levels in adipose tissue. Rats fed cholic acid (1% of chow wt/wt) for 2 weeks did not gain weight as rapidly as pair-fed control animals. Despite the lower weight, normalized leptin mRNA levels were 24% greater in cholic acid-fed rats compared with controls. Conversely, cholestyramine, a bile acid sequestrant, in chow (5% wt/wt) resulted in a 26% decline in leptin mRNA. Ligation of the common bile duct or chronic biliary diversion, experimental manipulations that decreased the intestinal concentration of bile salts, decreased leptin gene expression by 30% and 50%, respectively. A fluid and electrolyte (F/E) solution with and without taurocholate (36 micromol/h x 100 g rat[-1]) was then infused for 12 hours into the duodenum in animals with chronic biliary diversion. Taurocholate infusion resulted in a fourfold increase in steady-state adipocyte leptin mRNA levels compared with F/E infusion. Intravenous infusion of taurocholate or incubation of cultured adipocytes with taurocholate had no effect on leptin mRNA levels. We conclude that bile acids upregulate leptin gene expression indirectly, probably via effects on the absorption of dietary lipids or the release of neurohumoral mediators.

Bile salts are intraduodenal stimulants of basal pancreatic secretion. This study aims to show whether the three main bile salts of human bile differ in their action on pancreatic secretion, and whether they enhance or inhibit each other after combined use. Furthermore, the effect on gastroenteropancreatic peptide release is evaluated. Twelve subjects were provided with a gastroduodenal double-lumen tube. Equimolar doses (0.6 mmol) of taurocholate (322 mg), taurodeoxycholate (313 mg), and a combination of both stimuli were given intraduodenally. Another 12 subjects received taurochenodeoxycholate (313 mg) instead of taurocholate. Volume, bicarbonate, trypsin, and lipase were determined in duodenal aspirates. Cholecystokinin, pancreatic polypeptide, and somatostatin were measured radioimmunologically in plasma samples. All bile salts and combinations exerted a significant hydrokinetic and ecbolic effect. The hydrokinetic response of the combined stimuli was significantly higher as compared with taurocholate and taurochenodeoxycholate, respectively. As far as concerns the ecbolic response, the difference was significant only for trypsin output as compared with taurochenodeoxycholate. Plasma cholecystokinin rose significantly only after the combined stimuli. Pancreatic polypeptide and somatostatin increased significantly after all stimuli, except pancreatic polypeptide after taurocholate. Combined use enhances the hydrokinetic and ecbolic effects of single bile salts. Cholecystokinin may, hereby, be involved as a mediator of the ecbolic effect. Pancreatic polypeptide release indicates cholinergic mechanisms as further mediators. As demonstrated by somatostatin release, counter-regulatory mechanisms are also triggered by intraduodenal bile salts.

Little is known about the mechanisms of: 1) biliary phosphatidylcholine (PC) secretion by the hepatocyte, 2) selectivity for biliary 1-palmitoyl-2-linoleoyl-PC (PLPC) secretion, and 3) exclusion of 1-stearoyl-2-arachidonyl-PC (SAPC) from bile. The experiments were designed to determine, in rats, whether selectivity (for PLPC and against SAPC) is influenced by bile acid hydrophobicity or secretion rate. We examined the effects of bile acid depletion and of ileal infusion of taurocholic acid, tauroursodeoxycholic acid, and taurochenodeoxycholic acid. Compared to bile acid depletion, infusion of each bile acid caused PLPC to decrease from 59% of bile PC to 48%, and SAPC to increase from 2.6% to 5%. Bile acid hydrophobicity had no effect on PC selectivity, but selectivity decreased to a moderate degree as total PC secretion increased. To determine whether selectivity is for preformed molecular species, we used a new method to isotopically label four species of hepatic PC. This was done by intravenous injection of PLPC and SAPC labeled in the linoleate (14C) and arachidonate (3H) moieties. Assuming rapid mixing of each PC species in the hepatocyte as supported by the specific activity data, bile SAPC and SLPC were derived entirely from hepatic preformed SAPC and SLPC; bile PLPC was from both preformed PLPC (55%) and an unlabeled input (45%, probably direct secretion of newly synthesized PLPC). In conclusion, the selective composition of bile PC is not related to bile acid hydrophobicity, but is partially lost as secretion increases within the physiologic range.

Background: Bile acids may stimulate the movement of hepatocyte vesicles and enhance their fusion with the biliary canaliculus. The present study examined the effects of various bile acids on the exocytosis of the contents of hepatocyte lysosomes into the biliary canaliculus., Methods: The effects of various bile acids on hepatocyte lysosome movement and on exocytosis of the contents of hepatocyte lysosomes into the biliary canaliculus were determined from the distribution of fluorescein isothiocyanate-dextran--labeled lysosomes in hepatocyte couplets and by quantitating biliary lysosomal enzyme output in rats., Results: Hydrophobic as well as hydrophilic and nonmicellar bile acids were found to stimulate to a similar degree the output of lysosomal enzymes into bile, indicating that bile acid-induced change of canalicular or lysosomal membrane fluidity is not responsible for enhanced exocytosis. The taurocholate-dependent increase in lysosomal enzyme excretion was completely blocked by either microtubule or microfilament inhibition, suggesting that these subcellular structures are involved in bile acid-dependent vesicular transport. Fluorescent microscopy studies showed that taurocholate causes a microtubule-dependent translocation of lysosomes towards the canaliculus in hepatocyte couplets, which occurred at the same time as increased output of lysosomal enzymes into bile., Conclusions: The results suggest that bile acids modulate vesicle traffic towards the canaliculus by a mechanism unrelated to bile acid interaction with the vesicle membrane.

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.

Control male Wistar rats with intact bile circulation, animals with a bile duct-right ureter fistula, and bile duct-right ureter fistula rats fed taurocholic acid (5.5 mg/day) were maintained on a cholesterol-free pellet diet and pulse labeled subcutaneously with radioactive cholesterol. Bile acid feeding did not interfere with the synthesis of cholesterol by the intestinal mucosa or by the whole body in spite of markedly lowering the production of bile acids. Of the total fecal cholesterol mass in bile fistula animals roughly 25% originated from plasma filtration and 75% was ascribed to local mucosal cholesterol synthesis.

The effect of five bile acids on biliary lipid secretion was studied in the pentobarbital-anesthetized cat. The dihydroxy acid, taurohyodeoxycholic acid, was indistinguishable from another dihydroxy acid, taurochenodeoxycholic acid, but secretion of both phospholipid and cholesterol was considerably reduced with two mono-keto dihydroxy acids, tauro-3alpha,12alpha-dihydroxy-7-keto-5beta-cholanoic acid and tauro-3alpha,7alpha-dihydroxy-12-keto-5beta-cholanoic acid. The effect of a trihydroxy bile acid, taurocholic acid was as previously described. The effect of the keto bile acids may be explained by the ability of these bile acids to solubilize lipid, but such an explanation is inadequate for the difference between di- and trihydroxy bile acids. An intracellular effect of bile acid is postulated.

Somatostatin was administered intravenously to male Wistar rats, recovered for 3 h from an anesthesia during which the common bile duct and jugular vein were cannulated. Different bile acid-secretory rates were obtained by infusion of saline, or of Na+-taurocholate (150 nmol/min/100 g body wt), or by 8-h bile depletion. At the dose of 2 micrograms/h/100 g body wt, somatostatin causes a prompt decrease of bile flow (about 30%) and of bile acid secretion (32%-47%). The bile acid-independent fraction of canalicular bile is more decreased than the one associated with bile acid secretion. The changes are dose dependent and show a saturation pattern, with half-maximal saturation already at 2.2 ng/min/100 g body wt. Despite this cholestasis, endogenous bilirubin secretion remained unchanged, pointing to different secretory mechanisms for bilirubin and bile acids. In the isolated and perfused liver, somatostatin displays an anticholeretic effect, proportional to the amount of Na+-taurocholate present in the system. Hepatic blood flow and O2 consumption remained constant during perfusion, and were not affected by somatostatin. The hepatic transport of bile acid, and the water and electrolyte secretion are directly affected by somatostatin, and the experimentally-induced cholestasis seems a new and suitable model for studying mechanisms of bile secretion.

The simultaneous oral administration of acetylsalicylic acid (64 mg per kg) and taurocholic acid (2.5 mM) to rats induced gastric hemorrhagic mucosal bleeding in 82.4% of animals compared with 29.7% of animals given acetylsalicylic acid alone. Taurodeoxycholic acid and glycocholic acid with acetylsalicylic acid also significantly increased the incidence of gastric hemorrhagic mucosal bleeding compared with the control animals, but cholic acid, chenodeoxycholic acid, and deoxycholic acid did not have a significant effect. Hemorrhagic mucosal lesions were not observed when the bile acids studied were administered alone. These results indicate a possible role for certain bile acids in the pathogenesis of gastric mucosal bleeding after the ingestion of aspirin.

Two distinct lipoprotein receptors can be expressed in the dog liver. One is the apolipoprotein (apo-) B,E receptor. This receptor binds apo-B-containing low density lipoproteins (LDL), as well as apo-E-containing lipoproteins, such as the cholesterol-induced high density lipoproteins (HDL(c)). The second hepatic lipoprotein receptor is the apo-E receptor. It binds apo-E HDL(c) and chylomicron remnants, but not LDL. The present studies were undertaken to determine whether short-term (acute) regulation of the two receptors can occur in response to perturbations in hepatic cholesterol metabolism. The design used three groups of experimental animals: (a) immature dogs (with both hepatic apo-B,E and apo-E receptors expressed), (b) adult dogs (with predominantly the apo-E receptor expressed and little detectable apo-B,E receptor binding activity), and (c) dogs treated with the bile acid sequestrant cholestyramine or those that have undergone biliary diversion (with apo-E receptors and induced apo-B,E receptors). In the first series of experiments, changes in hepatic lipoprotein receptor expression were studied by delivering cholesterol to the liver via intestinal lymph lipoproteins. Dog lymph (5-11 mg of triglycerides/min per kg of body weight, 0.15-0.3 mg of cholesterol/min per kg) or saline were infused intravenously for 6-8 h into matched pairs of dogs. Serial liver biopsies were obtained at intervals of 1-2 h. A progressive loss of specific (calcium-dependent) binding of LDL was seen in hepatic membranes from both immature and cholestyramine-treated dogs. After 4-6 h of lymph infusion, almost no apo-B,E receptor binding could be detected. The decrease in binding of apo-E HDL(c) to the same membranes was much less pronounced, and could be explained by a loss of binding of HDL(c) to the apo-B,E receptor; there was little or no effect on apo-E receptor binding. In the second series of experiments, the effects of a diminished hepatic demand for cholesterol on lipoprotein receptor expression were studied by suppressing bile acid synthesis. The bile acid taurocholate (2-3 mumol/kg per min) was infused intravenously over a 6-h interval. This resulted in a progressive loss of LDL binding to liver membranes of immature or cholestyramine-treated dogs. The infusion of taurocholate for 6 h did not significantly alter the expression of the apo-E receptor binding activity, whereas apo-B,E receptor activity was rapidly down-regulated. Preparation of a bile fistula in adult dogs markedly induced the expression of the apo-B,E receptor. In this state, the binding activity of the apo-B,E receptor could be almost totally abolished by reinfusion of taurocholate for 6 h, without profoundly affecting apo-E receptor binding. Evidence from the analysis of plasma lipoprotein patterns and tissue culture reactivity suggested that changes in assayed hepatic lipoprotein receptor activity occurred in concert with changes in plasma lipoproteins.The results indicate that the two canine hepatic lipoprotein receptors differ in their metabolic regulation. The apo-B,E receptor responds rapidly to changes in hepatic requirements for cholesterol. The apo-E receptor appears to be more refractory to acute regulation. The rapidity of the changes in the activity of the apo-B,E receptor (within 2-4 h) suggests that the binding activity of this receptor may be regulated by factors independent of protein synthesis.

Bile acid-independent secretion and the choleretic response to taurocholate were determined in rhesus monkeys fitted with indwelling silastic cannulas in the common bile ducts. Bile acids were infused intravenously in random order at 3.5, 7.0, or 10.5 mumol/min for 1.5 h each. When data were analyzed with a single regression line, bile flow increased in proportion to the level of bile acid secretion, although the y-intercepts (the conventional measurement of bile acid-independent secretion) varied widely (77.9+/-40.9 ml/24 h). The variation in y-intercepts was observed between animals and with repeated studies in the same animal and could not be explained by sex differences or the effects of the indwelling silastic cannulas, but seemed to be related to the order of bile acid infusion. With only two taurocholic acid infusion rates (7.0 and 3.5 mumol/min), [(14)C]erythritol clearance was greater per mole of secreted bile acid when the initial bile acid infusion was at the high level, but approached zero at low bile acid secretion rates, which suggests that so-called bile acid-independent canalicular flow is closely related to bile acid secretion or is small in size. The augmentation in [(14)C]erythritol clearance when the high infusion rate was given first was also associated with an increase in biliary clearance of [(3)H]inulin, which indicates that the premeability to inulin was also enhanced. Identical experiments which substituted equimolar infusions of a nonmicelle-forming bile acid (taurodehydrocholate) for taurocholate failed to demonstrate any difference in choleretic response or biliary clearance of [(3)H]inulin with the order of bile acid infusion. These experiments demonstrate that a micelleforming bile acid, taurocholate, can increase the permeability of the biliary system to large molecular weight solutes and simultaneously modify the y-intercept and the volume of bile secreted in response to the transported bile acid. Taurocholate may, therefore, modify its own choleretic response, perhaps by altering the structure or function of bile secretory membranes, and appears to be a major determinant of so-called bile acid-independent flow in rhesus monkeys.

By correlating morphological observations with quantitative measurements of net water transport, we determined whether bile salts altered colonic absorptive cells. Epithelial alteration was equivocal and water absorption was uninhibited during infusions of 1 mM deoxycholate or of concentrations of taurocholate less than 10 mM. In contrast, 3 mM deoxycholate and greater than 10 mM taurocholate caused severe altertion of colonic epithelium and inhibited water absorption. These studies suggest that bile salts in the low concentrations normally found within the colon have little effect on colonic structure or water absorption. On the other hand, abnormally high concentrations of bile salts do alter colonic mucosal structure and function.

These studies were undertaken to characterize the role of bile salt hydrophobicity in determining the rate of cholesterol recruitment from the liver. Using an in vivo rat model in which the acquisition of hepatic cholesterol from chylomicron remnants, low-density lipoproteins, and de novo synthesis was measured and kept constant, it was found that the amount of sterol recruited from the liver cell increased progressively as the liver was probed with a constant infusion of progressively more hydrophobic bile salts. The absolute secretion rate of both cholesterol and phospholipid increased nearly 50% as the hydrophobic index of the bile salts traversing the liver increased from 1.7 to 4.5, but the ratio of cholesterol to phospholipid secreted in bile remained nearly constant. Thus, when cholesterol entry into the hepatocyte via lipoproteins and de novo cholesterol synthesis is constant, the mass of cellular cholesterol recruited into the bile is directly proportional to the hydrophobic-hydrophilic balance of the secreted bile salts.

The regulation of bile acid synthesis was studied (i) in intact or colectomized rats receiving cholate or taurocholate as a dietary supplement and (ii) in experiments using chow-fed animals with a graded intravenous or intraduodenal taurocholate infusion. After the 2-week diet period a bile fistula was established and rates of taurocholate, tauromuricholate and taurochenodeoxycholate secretion were quantitated by high-performance liquid chromatography. During the infusion experiments taurocholate production was calculated from the difference in specific activity of [14C]taurocholate between infusate and bile, whereas tauromuricholate and taurochenodeoxycholate synthesis was derived directly from their secretion rates after pool depletion. Both the 0.5% cholate and taurocholate diet suppressed tauromuricholate and taurochenodeoxycholate secretion nearly totally, but only cholate led to a prolonged inhibition taurocholate synthesis. The diets stimulated total bile acid secretion and expanded the total bile acid pool size 2- to 3-fold, but they also prompted a dramatic increase in the biliary secretion of taurodeoxycholate. In contrast, colectomized animals did not secrete taurodeoxycholate following the cholate diet and, despite a comparable increase in bile acid pool size, tauromuricholate and taurochenodeoxycholate secretion was inhibited to a lesser extent. In addition, the rate of bile acid secretion and synthesis was significantly enhanced when compared to that of intact rats. To determine whether taurocholate affected bile acid synthesis directly, the bile acid was infused intravenously or intraduodenally at varying rates up to 300 mumoles per kg per hr for 54 hr, i.e. a rate exceeding normal total bile acid secretion in these acute bile fistula animals nearly 3-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Olsalazine is a novel compound presently under development for the treatment of ulcerative colitis. Olsalazine sometimes causes diarrhoea; one of the possible explanations could be an increased load of bile acids in the colon. Bile acid ileostomy output was therefore measured enzymatically and after oral administration of tauro-23-[75Se]selena-25-homocholic acid (SeHCAT) in eight subjects during intake of placebo or olsalazine. The bile acid output showed great individual variations during both treatment periods, but there was no indication that olsalazine interfered with bile acid handling in the terminal ileum.