Depletion of Bile Acids and Bilirubin in Dogs with Biliary Obstruction by Plasmaperfusion of Usp-Charcoal-Coated Glass Beads

1980 ◽  
Vol 3 (5) ◽  
pp. 281-285 ◽  
Author(s):  
B.H. Lauterburg ◽  
E.R. Dickson ◽  
A.A. Pineda ◽  
H.F. Taswell

Patients with severe, inoperable cholestasis and intractable pruritus not responding to conventional medical therapy might benefit from a depletion of their bile acid pool by sorbent perfusion since accumulated bile acids are possibly responsible for their itching. In vitro, USP-charcoal-coated glass beads removed bile acids from human plasma far better than any other sorbent tested. In order to demonstrate the safety and efficacy of charcoal plasmaperfusion in vivo, five dogs underwent plasmapheresis one week following cholecystectomy and bile duct ligation, and 2.2 ± 0.2 (x̄ ± SD) times their plasma volume was passed over a column containing 400 ml of charcoal-coated glass beads prior to reinfusion. During the procedure the plasma bile acid concentration was reduced by 40.2 ± 4.0% and the bilirubin level by 48.2 ± 3.3%. The columns, whose capacity was far from being saturated, retained 1.3 ± 0.4 times the pre-perfusion plasma pool of bile acids (1.1 ± 0.2 for bilirubin) suggesting that substantial amounts of bile acids and bilirubin were mobilized from tissue stores. The procedure was well tolerated by the animals and might have promising clinical applications.

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stef De Lombaerde ◽  
Ken Kersemans ◽  
Sara Neyt ◽  
Jeroen Verhoeven ◽  
Christian Vanhove ◽  
...  

Introduction. An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n=3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c.) and high radiochemical purity (>99%); 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.


2020 ◽  
Vol 21 (21) ◽  
pp. 8168
Author(s):  
Andreas Schmid ◽  
Jonas Gehl ◽  
Miriam Thomalla ◽  
Alexandra Hochberg ◽  
Anja Kreiß ◽  
...  

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system.


1991 ◽  
Vol 280 (2) ◽  
pp. 373-377 ◽  
Author(s):  
S Dueland ◽  
J Reichen ◽  
G T Everson ◽  
R A Davis

We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct ligation decreased by about 30% both the amount of microsomal cytochrome P-450 in the liver and the elimination of aminopyrine in vivo, a reliable index in vivo of microsomal mixed-function oxidase activity. Cholesterol and bile acid contents in livers of bile-duct-ligated rats were doubled compared with sham-operated controls. Despite the increase in the contents of cholesterol and bile acids in liver, activities of the respective rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, were doubled. Serum concentrations of bile acids and free cholesterol increased 25- and 4-fold respectively. The large increase in serum bile acids was associated with a 380-fold increase in the urinary excretion of bile acids. Although there is a general decrease in cytochrome P-450 content and drug metabolism involving cytochrome P-450-containing hydroxylases, the activity of cholesterol 7 alpha-hydroxylase, also a cytochrome P-450-containing enzyme, is actually increased. These data show that complete obstruction of the bile duct results in the selective impairment of microsomal cytochrome P-450. Increased activity of 7 alpha-hydroxylase, bile acid synthesis and urinary excretion provides an alternative excretory pathway that helps to maintain cholesterol homoeostasis when the biliary excretory pathway is eliminated.


1982 ◽  
Vol 5 (3) ◽  
pp. 181-184 ◽  
Author(s):  
Ad van Berlo ◽  
Ad Verkooyen ◽  
A. Tangerman

A hemoperfusion system has been developed in wich very small charcoal particles (average diameter 40 μm) are embedded and immobilized in a collodion film (Filmadsorber). In vitro studies revealed that the absorption of bile acids by these small charcoal particles is superior to that by larger ones (size: 0.5 to 5 mm) as used in commercially available adsorbers. In vivo studies confirmed these results: dogs with ligated bile ducts were subjected to hemoperfusion through different types of charcoal adsorbers. Bile acid clearances of filmadsorbers containing less charcoal than the commercials were significantly higher.


1987 ◽  
Vol 73 (4) ◽  
pp. 343-350 ◽  
Author(s):  
A. Lanzini ◽  
W. J. F. Fitzpatrick ◽  
M. G. Pigozzi ◽  
T. C. Northfield

1. Studies were carried out in vitro using an ultracentrifugation method to quantify bile acid binding to the different components of a Lundh test meal, and to determine what factors influence bile acid binding to one of the components (casein). We validated the ultracentrifugation method by showing good agreement with the equilibrium dialysis method. Studies were carried out in vivo on jejunal aspirate from 10 ileal resection patients in order to determine whether bile acid binding to casein could be demonstrated, and whether this influenced aqueous-phase bile acid and fatty acid concentrations. 2. In vitro, the Lundh test meal was found to adsorb bile acid. The protein content of the meal (casein) alone accounted for this binding, which was abolished by use of casein hydrolysate. The binding to casein was a saturable process. Both binding affinity and binding capacity were significantly greater for taurocholate at pH 4.5 than at pH 6.5, and for dihydroxylated than for trihydroxylated bile acid, suggesting that hydrophobic bonding was involved. 3. In vivo, jejunal samples aspirated at pH > 6 from 10 ileal resection patients showed 25% binding of bile acid to protein. On substitution of amino acids for casein, mean binding was reduced to 16% (P < 0.05), residual binding being attributed to endogenous protein. This was associated with an increase in fatty acid solubilization from 28% to 60% (P < 0.025). 4. These findings suggest that protein binding may have a critical effect on aqueous-phase bile acid and fatty acid concentrations in certain patients with a reduced total bile acid concentration as in ileectomy steatorrhoea, and in patients with defective lipolysis as in pancreatic insufficiency. This finding may provide an additional rationale for the use of elemental diets in severely ill patients with steatorrhoea.


1992 ◽  
Vol 89 (6) ◽  
pp. 1981-1987 ◽  
Author(s):  
H U Marschall ◽  
H Matern ◽  
H Wietholtz ◽  
B Egestad ◽  
S Matern ◽  
...  
Keyword(s):  

2021 ◽  
Author(s):  
Akhil A. Vinithakumari ◽  
Belen G. Hernandez ◽  
Sudeep Ghimire ◽  
Seidu Adams ◽  
Caroline Stokes ◽  
...  

Clostridioides difficile is an antibiotic-resistant bacterium that causes serious, toxin-mediated enteric disease in humans and animals. Gut dysbiosis and resultant alterations in the intestinal bile acid profile play an important role in the pathogenesis of C. difficile infection (CDI). Restoration of the gut microbiota and re-establishment of bacterial bile acid metabolism using fecal microbiota transplantation (FMT) has been established as a promising strategy against this disease, although this method has several limitations. Thus, a more defined and precise microbiota-based approach using bacteria that biotransform primary bile acids into secondary bile acids could effectively overcome these limitations and control CDI. Therefore, a screening pipeline was developed to isolate bile acid converting bacteria from fecal samples. Dogs were selected as a model CDI-resistant microbiota donor for this pipeline, which yielded a novel Peptacetobacter hiranonis strain that possesses unique anti-C. difficile properties, and both bile acid deconjugation and 7-α dehydroxylating activities to perform bile acid conversion. The screening pipeline included a set of in vitro tests along with a precision in vivo gut colonization and bile acid conversion test using altered Schadler flora (ASF) colonized mice. In addition, this pipeline also provided essential information on the growth requirements for screening and cultivating the candidate bacterium, its survival in a CDI predisposing environment, and potential pathogenicity. The model pipeline documented here yielded multiple bile acid converting bacteria, including a P. hiranonis isolate with unique anti-C. difficile biotherapeutic potential, which can be further tested in subsequent preclinical and human clinical trials.


1983 ◽  
Vol 245 (1) ◽  
pp. G72-G77
Author(s):  
B. Seetharam ◽  
M. Jimenez ◽  
D. H. Alpers

Human bile or commercially available bile acids bind [57Co]cobalamin (Cbl) due to the presence of "R"-type binders, which are normally present in the former and present as a contaminant in the latter. The competition of these R proteins for the binding of Cbl by intrinsic factor (IF) could explain the in vivo inhibition attributed previously to the bile acids themselves. R protein seems to be involved in the inhibition of Cbl binding because protease digestion of either bile or bile acid abolishes the Cbl binding ability. Moreover, antibody to R protein abolishes the inhibition. Bile or bile acids do not have a direct effect on either purified IF or the IF-Cbl receptor molecule, even though bile acids increase the attachment of IF-[57Co]Cbl to ileal brush-border membranes. These data demonstrate two steps where components of bile could affect Cbl absorption: the binding of Cbl to IF and of IF-Cbl to its ileal receptor. It is not clear whether these in vitro phenomena are important for the normal absorption of Cbl in vivo.


2005 ◽  
Vol 288 (1) ◽  
pp. G60-G66 ◽  
Author(s):  
Hai Li ◽  
Frank Chen ◽  
Quan Shang ◽  
Luxing Pan ◽  
Benjamin L. Shneider ◽  
...  

The regulation of the rabbit apical sodium-dependent bile acid transporter (ASBT) was studied both in vivo and in vitro. New Zealand White rabbits were fed 0.5% deoxycholic acid (DCA) or SC-435, a competitive ASBT inhibitor, for 1 wk. In DCA-fed rabbits, ASBT expression was repressed, associated with activated FXR, and evidenced by increased ileal short heterodimer partner (SHP) mRNA. Feeding SC-435 to the rabbits blocked bile acid absorption, decreased SHP mRNA, and increased ASBT expression. A 1.9-kb rabbit ASBT 5′-flanking region (promoter) was cloned, and a cis-acting element for α-fetoprotein transcription factor (FTF) was identified (−1166/ −1158). The effects of transcriptional factors and different bile acids on the rabbit ASBT promoter were studied in Caco-2 cells. FTF stimulated the rabbit ASBT promoter activity fourfold but not after the FTF binding site was deleted from the promoter. Increasing the SHP protein notably inhibited FTF-dependent trans-activation of rabbit ASBT. Adding hydrophobic bile acids deoxycholic acid, chenodeoxycholic acid, and cholic acid, activating ligands for FXR, inhibited rabbit ASBT promoter activity in Caco-2 cells, but this inhibitory effect was abolished after the FTF binding site was deleted. Ursodeoxycholic acid and ursocholic acid, nonactivating ligands for FXR, did not repress ASBT promoter activity. Thus the rabbit ASBT promoter is negative-feedback regulated by bile acids via a functional FTF binding site. Only FXR-activating ligands can downregulate rabbit ASBT expression through the regulatory cascade FXR-SHP-FTF.


2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Zhe Wang ◽  
Xu-Ling Li ◽  
Kin-Fong Hong ◽  
Ting-Ting Zhao ◽  
Rui-Xue Dong ◽  
...  

Astragalus Radix is one of the common traditional Chinese medicines used to treat diabetes. However, the underlying mechanism is not fully understood. Flavones are a class of active components that have been reported to exert various activities. Existing evidence suggests that flavones from Astragalus Radix may be pivotal in modulating progression of diabetes. In this study, total flavones from Astragalus Radix (TFA) were studied to observe its effects on metabolism of bile acids both in vivo and in vitro. C57BL/6J mice were treated with STZ and high-fat feeding to construct diabetic model, and HepG2 cell line was applied to investigate the influence of TFA on liver cells. We found a serious disturbance of bile acids and lipid metabolism in diabetic mice, and oral administration or cell incubation with TFA significantly reduced the production of total cholesterol (TCHO), total triglyceride, glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), and low-density lipoprotein (LDL-C), while it increased the level of high-density lipoprotein (HDL-C). The expression of glucose transporter 2 (GLUT2) and cholesterol 7α-hydroxylase (CYP7A1) was significantly upregulated on TFA treatment, and FXR and TGR5 play pivotal role in modulating bile acid and lipid metabolism. This study supplied a novel understanding towards the mechanism of Astragalus Radix on controlling diabetes.


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