scholarly journals Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 281 ◽  
Author(s):  
Simon Hohenester ◽  
Veronika Kanitz ◽  
Andreas E. Kremer ◽  
Coen C. Paulusma ◽  
Ralf Wimmer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Bile Salt ◽  
Bile Salts ◽  
Collagen Deposition ◽  
Human Bile ◽  
Hepatic Expression ◽  
Cell Accumulation ◽  
Hepatocellular Cholestasis ◽  
Specific Contribution

Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1G308V/G308V mice, increased hepatic expression of αSMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.

scholarly journals Studies on the interactions between bile salts and food emulsifiers under in vitro duodenal digestion conditions to evaluate their bile salt binding potential

2019 ◽  
Vol 174 ◽  
pp. 493-500 ◽  
Author(s):  
Julieta N. Naso ◽  
Fernando A. Bellesi ◽  
Víctor M. Pizones Ruiz-Henestrosa ◽  
Ana M.R. Pilosof
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Binding Potential ◽  
Food Emulsifiers

Effect of intestinal resection on bile salt absorption in dogs

1965 ◽  
Vol 208 (2) ◽  
pp. 363-369 ◽  
Author(s):  
M. R. Playoust ◽  
Leon Lack ◽  
I. M. Weiner
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Enterohepatic Circulation ◽  
Sodium Taurocholate ◽  
Intestinal Resection ◽  
High Fat ◽  
Salt Absorption ◽  
Complete Failure ◽  
Fat Meal

The efficiency of intestinal absorption of bile salts was evaluated by studying the rate of disappearance of radioactivity from the bile of dogs after the intravenous administration of sodium taurocholate-24-C14. Bile was sampled through an indwelling tube in the gall bladder. One day after a high-fat meal normal dogs retained 48% of the radioactivity; dogs with resection of the jejunum retained 48%, whereas those with resection of the ileum retained only 3% in the bile. This is consistent with previous observations that the ileum is the site of bile salt absorption in vitro and in anesthetized animals. Animals with resection of the ileum exhibited significant steatorrhea; however, three-fourths of the ingested fat was absorbed in spite of almost complete failure to absorb bile salts. This indicates that fat and bile salts are not normally absorbed together. Elimination of enterohepatic circulation of bile salts by resection of the ileum contributes to the observed steatorrhea.

scholarly journals Purification, characterization and in vitro bile salt-binding capacity of polysaccharides from Armillaria mellea mushroom

2019 ◽  
Vol 37 (No. 1) ◽  
pp. 51-56 ◽  
Author(s):  
Chonghui Yue ◽  
Xiaodan Zang ◽  
Chao Chen ◽  
Liangwei Dong ◽  
Yanqiu Liu ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Binding Capacity ◽  
Monosaccharide Composition ◽  
Composition Analysis ◽  
Enzymatic Extraction ◽  
Armillaria Mellea ◽  
Ethanol Precipitation ◽  
Ultrasound Assisted

The crude polysaccharides from Armillaria mellea were obtained with an ultrasound assisted enzymatic extraction and ethanol precipitation. Two polysaccharide fractions were obtained by ethanol precipitation, which were named AMP-1 and AMP-2. The results of the monosaccharide composition analysis indicated that AMP-1 was composed of mannose, rhamnose, glucose, galactose, arabinose and fucose and that AMP-2 was composed of mannose, rhamnose, glucose, galactose and fucose. Glucose and galactose were the main monosaccharide fractions. The protein and nucleic acid contents in AMP-1 and AMP-2 were detected by using ultraviolet and infrared spectroscopy. The bile salt-binding capacities of the polysaccharide samples were studied in vitro. In comparison with lentinan (LP), AMP-1 and AMP-2 showed increased bile salt-binding capacity. AMP-1 showed the highest binding capacity against all the bile salts. The findings presented in this study highlight the potential of the A. mellea polysaccharides as a natural hypolipidaemic agent.

scholarly journals In Vitro Hypocholesterolemic Effect of Coffee Compounds

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 437
Author(s):  
Filipe Manuel Coreta-Gomes ◽  
Guido R. Lopes ◽  
Cláudia P. Passos ◽  
Inês M. Vaz ◽  
Fernanda Machado ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Soluble Fiber ◽  
Hexane Extraction ◽  
Selective Precipitation ◽  
Food Ingredients ◽  
Espresso Coffee ◽  
Coffee Lipids ◽  
Cholesterol Solubility

(1) Background: Cholesterol bioaccessibility is an indicator of cholesterol that is available for absorption and therefore can be a measure of hypocholesterolemic potential. In this work, the effect of commercial espresso coffee and coffee extracts on cholesterol solubility are studied in an in vitro model composed by glycodeoxycholic bile salt, as a measure of its bioaccessibility. (2) Methods: Polysaccharide extracts from coffees obtained with different extraction conditions were purified by selective precipitation with ethanol, and their sugars content were characterized by GC-FID. Hexane extraction allowed us to obtain the coffee lipids. Espresso coffee samples and extracts were tested regarding their concentration dependence on the solubility of labeled 13C-4 cholesterol by bile salt micelles, using quantitative 13C NMR. (3) Results and Discussion: Espresso coffee and coffee extracts were rich in polysaccharides, mainly arabinogalactans and galactomannans. These polysaccharides decrease cholesterol solubility and, simultaneously, the bile salts’ concentration. Coffee lipid extracts were also found to decrease cholesterol solubility, although not affecting bile salt concentration. (4) Conclusions: Coffee soluble fiber, composed by the arabinogalactans and galactomannans, showed to sequester bile salts from the solution, leading to a decrease in cholesterol bioaccessibility. Coffee lipids also decrease cholesterol bioaccessibility, although the mechanism of action identified is the co-solubilization in the bile salt micelles. The effect of both polysaccharides and lipids showed to be additive, representing the overall effect observed in a typical espresso coffee. The effect of polysaccharides and lipids on cholesterol bioaccessibility should be accounted on the formulation of hypocholesterolemic food ingredients.

scholarly journals Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiegen Chen ◽  
Josepmaria Argemi ◽  
Gemma Odena ◽  
Ming-Jiang Xu ◽  
Yan Cai ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Mononuclear Cells ◽  
Lipocalin 2 ◽  
Advanced Fibrosis ◽  
Hepatic Expression ◽  
Gene Sets ◽  
Short Term Mortality ◽  
Human Livers

Abstract Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2−/− mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2−/− mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.

Comparison of In Vitro Binding of Bile Salt by Pectins from Various Sources

2012 ◽  
Vol 506 ◽  
pp. 274-277 ◽  
Author(s):  
K. Cheewatanakornkool ◽  
A. Chaidedgumjorn ◽  
U. Sotanaphun ◽  
S. Limsirichaikul ◽  
C. Wessapan ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Serum Cholesterol Level ◽  
Sodium Deoxycholate ◽  
Sodium Cholate ◽  
Experimental Animals ◽  
Hypocholesterolemic Action ◽  
Acid Reaction ◽  
Layer Chromatography

Binding of bile salts by dietary fiber is believed to promote their excretion and hence to reduce the serum cholesterol level in man and experimental animals. In this study, the binding efficiency of soluble pectin from various sources, i.e., apple, citrus and pomelo, was examined. Sodium deoxycholate and sodium cholate hydrate were used as a model to represent bile salt in human body. The binding efficiency was assayed by acid reaction, thin layer chromatography (TLC) and enzyme cycling method. The results demonstrated that enzyme cycling method was the most suitable for assaying the in-vitro binding of bile salts while the TLC was not very sensitive, i.e., low amount of bile salts cannot be detected by TLC. Excess pectin from binding test could also interfere the acid reaction method even though the centrifugation was used to remove the excess pectin. When the concentration of pectin was increased, the binding efficiency with sodium deoxycholate increased. However, at 1% w/w of pectin, the binding efficiency decreased. The exception is for pomelo pectin in which the binding efficiency increased when the pectin concentration increased. With sodium cholate hydrate, only slight difference in binding efficiency was observed for all types and concentrations of pectin. The results indicate that the ability to bind bile salts of pectin might be responsible for its hypocholesterolemic action observed in experimental animals and humans.

scholarly journals Bile Salt Hydrolase of Bifidobacterium longum—Biochemical and Genetic Characterization

2000 ◽  
Vol 66 (6) ◽  
pp. 2502-2512 ◽  
Author(s):  
Hiroshi Tanaka ◽  
Honoo Hashiba ◽  
Jan Kok ◽  
Igor Mierau
Keyword(s):  
Molecular Weight ◽  
Amino Acid ◽  
Bile Salt ◽  
Bile Salts ◽  
Bifidobacterium Longum ◽  
Bacillus Sphaericus ◽  
Site Directed Mutagenesis ◽  
Bile Salt Hydrolase ◽  
Ph Optimum ◽  
Human Bile

ABSTRACT A bile salt hydrolase (BSH) was isolated from Bifidobacterium longum SBT2928, purified, and characterized. Furthermore, we describe for the first time cloning and analysis of the gene encoding BSH (bsh) in a member of the genusBifidobacterium. The enzyme has a native molecular weight of 125,000 to 130,000 and a subunit molecular weight of 35,024, as determined from the deduced amino acid sequence, indicating that the enzyme is a tetramer. The pH optimum of B. longum BSH is between 5 and 7, and the temperature optimum is 40°C. The enzyme is strongly inhibited by thiol enzyme inhibitors, indicating that a Cys residue is likely to be involved in the catalytic reaction. The BSH ofB. longum can hydrolyze all six major human bile salts and at least two animal bile salts. A slight preference for glycine-conjugated bile acids was detected based on both the specificity and the Km values. The nucleotide sequence of bsh was determined and used for homology studies, transcript analysis, and construction and analysis of various mutants. The levels of homology with BSH of other bacteria and with penicillin V acylase (PVA) of Bacillus sphaericus were high. On the basis of the similarity of BSH and PVA, whose crystal structure has been elucidated, BSH can be classified as an N-terminal nucleophile hydrolase with Cys as the N-terminal amino acid. This classification was confirmed by the fact that a Cys1Ala exchange by site-directed mutagenesis resulted in an inactive protein. Reverse transcription-PCR experiments revealed that bsh is part of an operon containing at least two genes, bsh andglnE (GlnE is glutamine synthetase adenylyltransferase). Two UV-induced BSH-negative mutants and one spontaneous BSH-negative mutant were isolated from B. longum SBT2928 cultures and characterized. These mutants had point mutations that inactivatedbsh by premature termination, frameshift, or amino acid exchange.

scholarly journals The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis

2017 ◽  
Vol 35 (3) ◽  
pp. 217-223 ◽  
Author(s):  
Jung-Chin Chang ◽  
Ulrich Beuers ◽  
Ronald P.J. Oude Elferink
Keyword(s):  
Bile Salt ◽  
Adenylyl Cyclase ◽  
Barrier Function ◽  
Bile Salts ◽  
Primary Biliary Cholangitis ◽  
Biliary Cirrhosis ◽  
Bicarbonate Secretion ◽  
Soluble Adenylyl Cyclase ◽  
Induced Apoptosis

Background: Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is a chronic fibrosing cholangiopathy with the signature of an autoimmune disease and features of intrahepatic cholestasis. Immunosuppressing treatments are largely unsuccessful. Responsiveness to ursodeoxycholic acid and reduced expression of anion exchanger 2 (AE2) on canalicular membranes and small bile ducts underline the importance of bicarbonate transportation in its disease mechanism. Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily conserved bicarbonate sensor that regulates apoptosis, barrier function and TNF signaling. Key Messages: The biliary epithelium defends against the toxic bile by bicarbonate secretion and by maintaining a tight barrier. Passive diffusion of weak acid conjugates (e.g. bile salts and other toxins) across plasma membrane is pH-dependent. Reduced AE2 expression results in both reduced bicarbonate secretion and accumulation of bicarbonate in the cells. Increased intracellular bicarbonate leads to increased sAC activity, which regulates bile salt-induced apoptosis. Reduced bicarbonate secretion causes more bile salts to enter cells, which further increase sAC activity by releasing intracellular Ca2+ store. In vitro studies demonstrate that inhibition of sAC not only corrects sensitization to bile salt-induced apoptosis as a result of AE2 down-regulation but also prevents bile salt-induced apoptosis altogether. Targeting sAC is also likely to slow down disease progression by strengthening the barrier function of biliary epithelia and by reducing oxidative stress as a result of chronic inflammation. Conclusions: sAC is a potential therapeutic target for PBC. More in vitro and in vivo studies are needed to understand how sAC regulates bile salt-induced apoptosis and to establish its therapeutic value in PBC and other cholestatic cholangiopathies.

scholarly journals A study of the physicochemical interactions between biliary lipids and chlorpromazine hydrochloride. Bile-salt precipitation as a mechanism of phenothiazine-induced bile secretory failure

1976 ◽  
Vol 153 (3) ◽  
pp. 519-531 ◽  
Author(s):  
M C Carey ◽  
P C Hirom ◽  
D M Small
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Water Soluble ◽  
Molar Ratio ◽  
Micellar Solutions ◽  
Membrane Phospholipids ◽  
Chlorpromazine Hydrochloride ◽  
Physicochemical Interactions ◽  
Cationic Detergents

Since chlorpromazine hydrochloride [2-chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride] is commonly implicated in causing bile-secretory failure in man and is secreted into bile, we have studied the physicochemical interactions of the drug with the major components of bile in vitro. Chlorpromazine hydrochloride molecules are amphiphilic by virtue of possessing a polar tertiary amine group linked by a short paraffin chain to a tricyclic hydrophobic part. At pH values below the apparent pK (pK'a 7.4) the molecules are water-soluble cationic detergents. We show that bile salts in concentrations above their critical micellar concentrations are precipitated from solution by chlorpromazine hydrochloride as insoluble 1:1 salt complexes. In the case of mixed bile-salt/phosphatidylcholine micellar solutions, however, the degree of precipitation is inhibited by the phospholipid in proportion to its mole fraction. With increases in the concentration of chlorpromazine hydrochloride or bile salt, micellar solubilization of the precipitated complexes results. Sonicated dispersions of the negatively charged phospholipid phosphatidylserine were also precipitated, but dispersions of the zwitterionic phospholipid phosphatidylcholine were not. Chlorpromazine hydrochloride efficiently solubilized these membrane phospholipids as mixed micellar solutions when the drug:phospholipid molar ratio reached 4:1. Polarizing-microscopy and X-ray-diffraction studies revealed that the precipitated complexes were amorphous and potentiometric studies confirmed the presence of a salt bond. Some dissociation of the complex occurred in the case of the most polar bile salt (Ks 0.365). As canalicular bile-salt secretion determines much of bile-water flow, we propose that complexing and precipitation of bile salts by chlorpromazine hydrochloride and its metabolites may be physicochemically related to the reversible bile-secretory failure produced by this drug.

scholarly journals The inhibitory effect of blood serum on hæmolysis

1923 ◽  
Vol 95 (665) ◽  
pp. 42-61 ◽  
Keyword(s):  
Blood Serum ◽  
Bile Salt ◽  
Bile Salts ◽  
Quantitative Methods ◽  
Sodium Taurocholate ◽  
Marked Change ◽  
Inhibitory Effect ◽  
Haemolytic Activity ◽  
Serum Globulin

It has been recognised for many years that blood serum has an inhibitory effect on the hæmolysis produced by many substances, notably saponin and bile salts. Ransom (1), in 1901, observing that cholesterol inhibits the action of saponin, attributed the inhibitory effect of serum to the contained cholesterol. The quantities of cholesterol used in his experiments are far greater than those which occur in serum, and the experiments are inconclusive for that reason. Bayer (2), in 1907, investigated the inhibitory effect produced by serum on the action of the bile salts. He found that cholesterol has no inhibitory effect, that lecithin produces inhibition, but not in the quantities that occur in blood, and that the proteins of the serum are responsible for the inhibition. He calls attention to the results of von Eisler (3), who states that serum globulin inhibits the action of staphalolysin and of tetanolysin, and also those of von Liebermann, who finds that hæmolysis by soaps is prevented by serum albumin (4). Bayer’s researches are, in the main, confirmed by Sellards (5). The investigations of Ludke (6) and of Scandaliato (7), who found that the inhibitory effect of serum is slightly increased after the injection of bile salts, may be mentioned. The conclusions of these authors are unreliable, since inadequate methods of measuring the amount of inhibition were used. References to various points in connection with the inhibition produced by serum in vivo and in vitro are to be found in the writer’s earlier papers (8, 9, 10). The Nature of the Inhibitory Substances . Before proceeding to the quantitative estimations, it is necessary to know which constituents of serum are responsible for the inhibition of saponin and bile salt hæmolysis respectively. Bayer’s results might be taken as conclusive were it not for two considerations: (1) Bayer filtered most of the solutions of bile salts, and lecithin-bile-salt mixtures, whose hæmolytic power he wished to determine, through a Berkefeld filter, and thereafter tested their hæmolytic activity. He states that this procedure has no effect on the time taken for these solutions to produce hæmolysis. This is a fallacy, for a solution of sodium taurocholate will not pass through a filter paper without losing some of its hæmolytic activity, while passage through a Berkefeld filter causes a very marked change indeed (10). It is therefore not permissible to regard the hæmolytic activity of a solution filtered in this way as identical with, or even corresponding to, the activity of an unfiltered solution; (2) Bayer used very rough quantitative methods—he refers to “slight hæmolysis,” “considerable hæmolysis,” etc., and, accordingly, would be able to detect only very marked degrees of inhibition. The same remark applies to the experiments of Sellards.

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