scholarly journals Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction

2021 ◽  
Vol 12 ◽  
Author(s):  
Tilman Sauerbruch ◽  
Martin Hennenberg ◽  
Jonel Trebicka ◽  
Ulrich Beuers
Keyword(s):  
Liver Cirrhosis ◽  
Bile Acid ◽  
Bile Acids ◽  
Enterohepatic Circulation ◽  
Vascular Dysfunction ◽  
Farnesoid X Receptor ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Circulatory Disturbance

The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.

Bacterial deconjugation and enterohepatic circulation of norursocholic acid conjugates in rats

1991 ◽  
Vol 261 (6) ◽  
pp. G1065-G1071
Author(s):  
J. Lillienau ◽  
B. Borgstrom
Keyword(s):  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Cecal Content ◽  
Acid Biosynthesis ◽  
Bile Acid Pool ◽  
Distal Small Intestine ◽  
Acid Pool ◽  
System 2 ◽  
Small Intestinal

Experiments were performed to define the metabolism of norusocholic acid (nUC) conjugates and to quantify to what extent the bile acid pool can be enriched in these bile acids. In vitro incubations of norusocholylglycine (nUCG) and -taurine (nUCT) with small intestinal or cecal content showed deconjugation with only cecal content. Cholylglycine (CG) was deconjugated by small intestinal and cecal content. Infusion of nUCG and CG showed that only a small proportion of nUCG was deconjugated after 24 h of enterohepatic circulation, whereas all CG was deconjugated. When nUCT was administered orally, deconjugation was shown to take place mainly in the cecum. Chronic feeding of nUCT enriched the bile acid pool with only 20% nUCT. We conclude that nUC conjugates are deconjugated primarily by bacteria in the cecum and colon, in contrast to CG, which, in addition to cecum and colon, is deconjugated in the distal small intestine. nUCT and its metabolites do not enrich in the circulating bile acid pool mainly for the following reasons: 1) nUC conjugates have a low affinity for the ileal transport system; 2) nUC, even if formed by deconjugation, is not passively absorbed at a sufficient rate; 3) the small amount of norursodeoxycholic acid formed from nUC is glucuronidated in the liver and glucuronide conjugates do not undergo enterohepatic circulation; and 4) nUC conjugates do not suppress bile acid biosynthesis.

Assessment of Gall-Bladder Storage Function in Man

1983 ◽  
Vol 65 (2) ◽  
pp. 185-191 ◽  
Author(s):  
R. P. Jazrawi ◽  
R. M. Kupfer ◽  
C. Bridges ◽  
A. Joseph ◽  
T. C. Northfield
Keyword(s):  
Bile Acid ◽  
Gall Bladder ◽  
Bile Acids ◽  
Saturation Index ◽  
Biliary Lipid ◽  
Fasting State ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Lipid Mass

1. We have validated a scintiscanning method for measuring fasting-state gall-bladder (GB) filling in man. 99mTc-labelled diethyl phenylcarbamoylmethyliminodiacetate (Tc-HIDA) was given intravenously, and 90 min later GB and gut activity were measured by using two isosensitive rectilinear scanning heads (anterior and posterior). Studies with a phantom GB in vitro, and studies in man in vivo, showed that the maximum error due to differences in isotope depth was 8%, compared with 300% when only one head was used. 2. By combining this technique with measurement of biliary lipid concentrations of fasting-state GB bile obtained by nasoduodenal intubation and intravenous cholecystokinin infusion, we were able to measure for the first time the total mass of all three biliary lipids in the GB. GB bile samples obtained in this way were divided into three consecutive portions of equal size in order to assess GB mixing. Bile acid pool size was also measured by isotope dilution. 3. We studied 12 healthy non-obese men. Fasting-state GB filling over 90 min (mean ± sem) was 54 ±8%. Biliary lipid mass in GB was 4.9 ±0.5 mmol for bile acids (67 ± 5% of the total bile acid pool), 1.6 ±0.2 mmol for phospholipid and 0.5 ± 0.1 mmol for cholesterol. The three consecutive portions of fasting GB bile gave values of 1.05 ± 0.07, 1.05 ± 0.06 and 1.03 ±0.10 for cholesterol saturation index (SI) and 6.6 ±1.1, 7.4 ± 1.6 and 6.5 ± 1.0 for Tc-HIDA c.p.m. × 1000 per mmol of bile acids. 4. The SI of fasting-state GB bile was significantly correlated with fasting-state GB filling (r = 0.63; P < 0.05). It was also correlated with cholesterol mass in GB (r = 0.64; P < 0.05), but not with bile acid and phospholipid mass. 5. We conclude that: (a) valid measurements of GB filling can be made in man by a simple scintiscanning technique employing 99mTc-HIDA as a biliary marker; (b) biliary lipid mass can also be measured if GB bile is obtained; (c) SI in health is in part determined by the degree of fasting-state GB filling, and in part by cholesterol mass in GB; (d) fasting-state GB content is well mixed in health.

scholarly journals Arbutin Alleviates the Liver Injury of α-Naphthylisothiocyanate-induced Cholestasis Through Farnesoid X Receptor Activation

2021 ◽  
Vol 9 ◽  
Author(s):  
Peijie Wu ◽  
Ling Qiao ◽  
Han Yu ◽  
Hui Ming ◽  
Chao Liu ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Protective Effect ◽  
Bile Acids ◽  
Liver Toxicity ◽  
Enterohepatic Circulation ◽  
Receptor Activation ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Cholestatic Diseases

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

scholarly journals Antibiotic-Induced Changes in Microbiome-Related Metabolites and Bile Acids in Rat Plasma

Metabolites ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 242
Author(s):  
Véronique de Bruijn ◽  
Christina Behr ◽  
Saskia Sperber ◽  
Tilmann Walk ◽  
Philipp Ternes ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Community Analysis ◽  
Rat Plasma ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Administration Routes ◽  
Plasma Metabolome ◽  
Induced Changes ◽  
Plasma Metabolite

Various environmental factors can alter the gut microbiome’s composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were compared to distinguish between microbiome-derived or -associated and systemic changes in the plasma metabolome. The resulting changes in the plasma metabolome were compared to the effects of a third reference compound, roxithromycin, which is readily bioavailable. A community analysis revealed that the oral administration of vancomycin and roxithromycin in particular leads to an altered microbial population. Antibiotic-induced changes depending on the administration routes were observed in plasma metabolite levels. Indole-3-acetic acid (IAA) and hippuric acid (HA) were identified as key metabolites of microbiome modulation, with HA being the most sensitive. Even though large variations in the plasma bile acid pool between and within rats were observed, the change in microbiome community was observed to alter the composition of the bile acid pool, especially by an accumulation of taurine-conjugated primary bile acids. In-depth investigation of the relationship between microbiome variability and their functionality, with emphasis on the bile acid pool, will be necessary to better assess the potential adverseness of environmentally induced microbiome changes.

Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated

2004 ◽  
Vol 286 (5) ◽  
pp. G730-G735 ◽  
Author(s):  
Guorong Xu ◽  
Lu-xing Pan ◽  
Hai Li ◽  
Quan Shang ◽  
Akira Honda ◽  
...  
Keyword(s):  
Bile Acid ◽  
Target Genes ◽  
Dietary Cholesterol ◽  
Farnesoid X Receptor ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Sprague Dawley Rats ◽  
Bile Acid Pool Size

Cholesterol feeding upregulates CYP7A1 in rats but downregulates CYP7A1 in rabbits. To clarify the mechanism responsible for the upregulation of CYP7A1 in cholesterol-fed rats, the effects of dietary cholesterol (Ch) and cholic acid (CA) on the activation of the nuclear receptors, liver X-receptor (LXR-α) and farsenoid X-receptor (FXR), which positively and negatively regulate CYP7A1, were investigated in rats. Studies were carried out in four groups ( n = 12/group) of male Sprague-Dawley rats fed regular chow (control), 2% Ch, 2% Ch + 1% CA, and 1% CA alone for 1 wk. Changes in mRNA expression of short heterodimer partner (SHP) and bile salt export pump (BSEP), target genes for FXR, were determined to indicate FXR activation, whereas the expression of ABCA1 and lipoprotein lipase (LPL), target genes for LXR-α, reflected activation. CYP7A1 mRNA and activity increased twofold and 70%, respectively, in rats fed Ch alone when the bile acid pool size was stable but decreased 43 and 49%, respectively, after CA was added to the Ch diet, which expanded the bile acid pool 3.4-fold. SHP and BSEP mRNA levels did not change after feeding Ch but increased 88 and 37% in rats fed Ch + CA. This indicated that FXR was activated by the expanded bile acid pool. When Ch or Ch + CA were fed, hepatic concentrations of oxysterols, ligands for LXR-α increased to activate LXR-α, as evidenced by increased mRNA levels of ABCA1 and LPL. Feeding CA alone enlarged the bile acid pool threefold and increased the expression of both SHP and BSEP. These results suggest that LXR-α was activated in rats fed both Ch or Ch + CA, whereas CYP7A1 mRNA and activity were induced only in Ch-fed rats where the bile acid pool was not enlarged such that FXR was not activated. In rats fed Ch + CA, the bile acid pool expanded, which activated FXR to offset the stimulatory effects of LXR-α on CYP7A1.

scholarly journals Increased cholesterol 7α-hydroxylase expression and size of the bile acid pool in the lactating rat

2008 ◽  
Vol 294 (4) ◽  
pp. G1009-G1016 ◽  
Author(s):  
Clavia Ruth Wooton-Kee ◽  
David E. Cohen ◽  
Mary Vore
Keyword(s):  
Bile Acid ◽  
Protein Expression ◽  
Mrna Expression ◽  
Bile Acids ◽  
Fold Increase ◽  
Bile Acid Pool ◽  
Hydrophobicity Index ◽  
Acid Pool ◽  
Bile Acid Transporters ◽  
Cholic Acids

Maximal bile acid secretory rates and expression of bile acid transporters in liver and ileum are increased in lactation, possibly to facilitate increased enterohepatic recirculation of bile acids. We determined changes in the size and composition of the bile acid pool and key enzymes of the bile acid synthetic pathway [cholesterol 7α-hydroxylase (Cyp7a1), sterol 27-hydroxylase (Cyp27a1), and sterol 12α-hydroxylase (Cyp8b1)] in lactating rats relative to female virgin controls. The bile acid pool increased 1.9 to 2.5-fold [postpartum (PP) days 10, 14, and 19–23], compared with controls. A 1.5-fold increase in cholic acids and a 14 to 20% decrease in muricholic acids in lactation significantly increased the hydrophobicity index. In contrast, the hepatic concentration of bile acids and small heterodimer partner mRNA were unchanged in lactation. A 2.8-fold increase in Cyp7a1 mRNA expression at 16 h (10 h of light) demonstrated a shift in the diurnal rhythm at day 10 PP; Cyp7a1 protein expression and cholesterol 7α-hydroxylase activity were significantly increased at this time and remained elevated at day 14 PP but decreased to control levels by day 21 PP. There was an overall decrease in Cyp27a1 mRNA expression and a 20% decrease in Cyp27a1 protein expression, but there was no change in Cyp8b1 mRNA or protein expression at day 10 PP. The increase in Cyp7a1 expression PP provides a mechanism for the increase in the bile acid pool.

scholarly journals A metabolic pathway for bile acid dehydroxylation by the gut microbiome

2019 ◽  
Author(s):  
Masanori Funabashi ◽  
Tyler L. Grove ◽  
Victoria Pascal ◽  
Yug Varma ◽  
Molly E. McFadden ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Lithocholic Acid ◽  
Primary Biliary Cholangitis ◽  
Bile Acid Pool ◽  
Secondary Bile Acid ◽  
Acid Pool ◽  
Road Map ◽  
Host Physiology

ABSTRACTThe gut microbiota synthesize hundreds of molecules, many of which are known to impact host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at ~500 μM and are known to block C. difficile growth1, promote hepatocellular carcinoma2, and modulate host metabolism via the GPCR TGR53. More broadly, DCA, LCA and their derivatives are a major component of the recirculating bile acid pool4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Despite the clear impact of DCA and LCA on host physiology, incomplete knowledge of their biosynthetic genes and a lack of genetic tools in their native producer limit our ability to modulate secondary bile acid levels in the host. Here, we complete the pathway to DCA/LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the 8-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes, conferring production of DCA and LCA on a non-producing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool, and provide a road map for deorphaning and engineering pathways from the microbiome as a critical step toward controlling the metabolic output of the gut microbiota.

scholarly journals Retention of Primary Bile Acids by Lupin Cell Wall Polysaccharides Under In Vitro Digestion Conditions

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2117 ◽  
Author(s):  
Naumann ◽  
Schweiggert-Weisz ◽  
Haller ◽  
Eisner
Keyword(s):  
Cell Wall ◽  
Bile Acid ◽  
Bile Acids ◽  
Molecular Interactions ◽  
Enterohepatic Circulation ◽  
In Vitro Digestion ◽  
Adsorptive Capacity ◽  
Cell Wall Polysaccharides ◽  
Dietary Fibres

Interference of dietary fibres with the enterohepatic circulation of bile acids is proposed as a mechanism for lowering cholesterol. We investigated how lupin hull and cotyledon dietary fibres interact with primary bile acids using an in vitro model under simulated upper gastrointestinal conditions. Cell wall polysaccharides were isolated and extracted to separate pectin-like, hemicellulosic, and lignocellulosic structures. Lupin hull consisted mainly of structural components rich in cellulose. The viscosity of the in vitro digesta of lupin hull was low, showing predominantly liquid-like viscoelastic properties. On the other hand, lupin cotyledon fibre retarded bile acid release due to increased viscosity of the in vitro digesta, which was linked with high contents of pectic polymers forming an entangled network. Molecular interactions with bile acids were not measured for the hull but for the cotyledon, as follows: A total of 1.29 µmol/100 mg DM of chenodesoxycholic acids were adsorbed. Molecular interactions of cholic and chenodesoxycholic acids were evident for lignin reference material but did not account for the adsorption of the lupin cotyledon. Furthermore, none of the isolated and fractionated cell wall materials showed a significant adsorptive capacity, thus disproving a major role of lupin cell wall polysaccharides in bile acid adsorption.

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