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Journal of Hepatology Feb 2021Many epithelia secrete bicarbonate-rich fluid to generate flow, alter viscosity, control pH and potentially protect luminal and intracellular structures from chemical... (Review)
Review
Many epithelia secrete bicarbonate-rich fluid to generate flow, alter viscosity, control pH and potentially protect luminal and intracellular structures from chemical stress. Bicarbonate is a key component of human bile and impaired biliary bicarbonate secretion is associated with liver damage. Major efforts have been undertaken to gain insight into acid-base homeostasis in cholangiocytes and more can be learned from analogous secretory epithelia. Extrahepatic examples include salivary and pancreatic duct cells, duodenocytes, airway and renal epithelial cells. The cellular machinery involved in acid-base homeostasis includes carbonic anhydrase enzymes, transporters of the solute carrier family, and intra- and extracellular pH sensors. This pH-regulatory system is orchestrated by protein-protein interactions, the establishment of an electrochemical gradient across the plasma membrane and bicarbonate sensing of the intra- and extracellular compartment. In this review, we discuss conserved principles identified in analogous secretory epithelia in the light of current knowledge on cholangiocyte physiology. We present a framework for cholangiocellular acid-base homeostasis supported by expression analysis of publicly available single-cell RNA sequencing datasets from human cholangiocytes, which provide insights into the molecular basis of pH homeostasis and dysregulation in the biliary system.
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Bicarbonates; Bile; Bile Ducts; Epithelium; Humans; Hydrogen-Ion Concentration; Secretory Pathway
PubMed: 33342564
DOI: 10.1016/j.jhep.2020.10.010 -
PloS One 2022Across Southeast Asia and China, more than 17000 Asian bears are kept under suboptimal conditions and farmed for their bile to meet the consumer demand for traditional...
Across Southeast Asia and China, more than 17000 Asian bears are kept under suboptimal conditions and farmed for their bile to meet the consumer demand for traditional medicine products. Years of unsterile and repetitive bile extraction contribute to the development of chronic sterile or bacterial cholecystitis, a pathology commonly diagnosed in formerly bile-farmed bears. In both human and veterinary medicine, the diagnostic value of the macroscopic bile examination for assessing gallbladder disease is unclear. The objective of this study is to identify the role of gallbladder bile color, viscosity, and turbidity, while comparing them with established markers of cholecystitis. Moreover, it aims to define the optimal duration of oral antibiotic treatment for chronic bacterial cholecystitis in bears associated with bile farming. Thirty-nine adult, formerly bile-farmed Asiatic black bears (Ursus thibetanus) were examined under anesthesia and underwent percutaneous ultrasound guided cholecystocentesis. A total of 59 bile samples were collected with 20 animals sampled twice to evaluate the therapeutic success. All bile aspirates were assessed macroscopically and microscopically followed by submission for bacterial culture and antimicrobial sensitivity. In the majority of bears, samples with cytological evidence of bactibilia lacked inflammatory cells and did not always correlate with positive bacterial cultures. The most common bacterial isolates were Enterococcus spp, Streptococcus spp and Escherichia coli. Based on our findings, the optimal duration of antibiotic treatment for chronic bacterial cholecystitis is 30 days. Moreover, unlike Gamma-glutamyl Transferase (GGT) and gallbladder wall thickness, the organoleptic properties of bile were found to be reliable markers of chronic gallbladder inflammation with color and turbidity indicating cholestasis. The current study highlights the importance of cholecystocentesis for the management of gallbladder disease and provides initial results on the possible diagnostic value of macroscopic bile examination.
Topics: Animals; Anti-Bacterial Agents; Bile; Cholecystitis; Gallbladder Diseases; Ursidae
PubMed: 35239687
DOI: 10.1371/journal.pone.0264391 -
Journal of Lipid Research Aug 2009In the past, bile acids were considered to be just detergent molecules derived from cholesterol in the liver. They were known to be important for the solubilization of... (Review)
Review
In the past, bile acids were considered to be just detergent molecules derived from cholesterol in the liver. They were known to be important for the solubilization of cholesterol in the gallbladder and for stimulating the absorption of cholesterol, fat-soluble vitamins, and lipids from the intestines. However, during the last two decades, it has been discovered that bile acids are regulatory molecules. Bile acids have been discovered to activate specific nuclear receptors (farnesoid X receptor, preganane X receptor, and vitamin D receptor), G protein coupled receptor TGR5 (TGR5), and cell signaling pathways (c-jun N-terminal kinase 1/2, AKT, and ERK 1/2) in cells in the liver and gastrointestinal tract. Activation of nuclear receptors and cell signaling pathways alter the expression of numerous genes encoding enzyme/proteins involved in the regulation of bile acid, glucose, fatty acid, lipoprotein synthesis, metabolism, transport, and energy metabolism. They also play a role in the regulation of serum triglyceride levels in humans and rodents. Bile acids appear to function as nutrient signaling molecules primarily during the feed/fast cycle as there is a flux of these molecules returning from the intestines to the liver following a meal. In this review, we will summarize the current knowledge of how bile acids regulate hepatic lipid and glucose metabolism through the activation of specific nuclear receptors and cell signaling pathways.
Topics: Animals; Bile; Bile Acids and Salts; Digestion; Enterohepatic Circulation; Fibroblast Growth Factors; Gastrointestinal Tract; Humans; Liver; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 19346331
DOI: 10.1194/jlr.R900007-JLR200 -
Gut Sep 1970
Review
Topics: Animals; Bile; Cholangiography; Cholecystography; Cholelithiasis; Dogs; Duodenal Ulcer; Gallbladder; Gastrectomy; Gastric Juice; Gastrins; Humans; Secretin; Vagotomy; Vagus Nerve
PubMed: 4919707
DOI: 10.1136/gut.11.9.799 -
Scientific Reports Apr 2020Despite the efforts of a number of research groups worldwide, we still have a poor understanding of the chemical nature of the fish kairomones which induce defensive...
Despite the efforts of a number of research groups worldwide, we still have a poor understanding of the chemical nature of the fish kairomones which induce defensive morphology, life history and behavior in their planktonic prey. Bile excreted by foraging fish play a crucial role in their signaling systems. Using high-performance liquid chromatography (HPLC), we revealed the presence of primary and secondary bile acids and bile salts in fish-conditioned water, similar as in carp bile. Upon exposure to either fish bile or commercially acquired bile salts, Daphnia demonstrated similar changes in life history and behavior as when exposed to fish kairomones. The synergic effect of the injured Daphnia alarm substance with fish bile on Daphnia life history is similar to the adaptive effect of the same alarm substance combined with fish kairomones. This strongly supports the view that fish bile or selected bile acids/salts may be responsible for the biological activity of kairomones.
Topics: Animals; Bile; Bile Acids and Salts; Carps; Chromatography, High Pressure Liquid; Pheromones
PubMed: 32341368
DOI: 10.1038/s41598-020-63456-z -
Nature Communications Nov 2023Normothermic machine perfusion (NMP) after static cold storage is increasingly used for preservation and assessment of human donor livers prior to transplantation....
Normothermic machine perfusion (NMP) after static cold storage is increasingly used for preservation and assessment of human donor livers prior to transplantation. Biliary viability assessment during NMP reduces the risk of post-transplant biliary complications. However, understanding of molecular changes in the biliary system during NMP remains incomplete. We performed an in-depth, unbiased proteomics analysis of bile collected during sequential hypothermic machine perfusion, rewarming and NMP of 55 human donor livers. Longitudinal analysis during NMP reveals proteins reflective of cellular damage at early stages, followed by upregulation of secretory and immune response processes. Livers with bile chemistry acceptable for transplantation reveal protein patterns implicated in regenerative processes, including cellular proliferation, compared to livers with inadequate bile chemistry. These findings are reinforced by detection of regenerative gene transcripts in liver tissue before machine perfusion. Our comprehensive bile proteomics and liver transcriptomics data sets provide the potential to further evaluate molecular mechanisms during NMP and refine viability assessment criteria.
Topics: Humans; Bile; Liver Transplantation; Proteome; Living Donors; Liver; Biliary Tract; Perfusion
PubMed: 38036513
DOI: 10.1038/s41467-023-43368-y -
Journal of Lipid Research Nov 2020Bile acids (BAs) have been established as ubiquitous regulatory molecules implicated in a large variety of healthy and pathological processes. However, the scope of BA...
Bile acids (BAs) have been established as ubiquitous regulatory molecules implicated in a large variety of healthy and pathological processes. However, the scope of BA heterogeneity is often underrepresented in current literature. This is due in part to inadequate detection methods, which fail to distinguish the individual constituents of the BA pool. Thus, the primary aim of this study was to develop a method that would allow the simultaneous analysis of specific C24 BA species, and to apply that method to biological systems of interest. Herein, we describe the generation and validation of an LC-MS/MS assay for quantification of numerous BAs in a variety of cell systems and relevant biofluids and tissue. These studies included the first baseline level assessment for planar BAs, including allocholic acid, in cell lines, biofluids, and tissue in a nonhuman primate (NHP) laboratory animal, , in healthy conditions. These results indicate that immortalized cell lines make poor models for the study of BA synthesis and metabolism, whereas human primary hepatocytes represent a promising alternative model system. We also characterized the BA pool of in detail. Our results support the use of NHP models for the study of BA metabolism and pathology in lieu of murine models. Moreover, the method developed here can be applied to the study of common and planar C24 BA species in other systems.
Topics: Animals; Bile; Bile Acids and Salts; Cells, Cultured; Chromatography, High Pressure Liquid; Hepatocytes; Humans; Macaca mulatta; Tandem Mass Spectrometry
PubMed: 32718973
DOI: 10.1194/jlr.D120000726 -
Poultry Science Jun 2014Avian bile is rich in matrix metalloproteinases (MMP), the enzymes that cleave extracellular matrix proteins such as collagens and proteoglycans. Changes in bile MMP...
Avian bile is rich in matrix metalloproteinases (MMP), the enzymes that cleave extracellular matrix proteins such as collagens and proteoglycans. Changes in bile MMP expression have been correlated with hepatic and gall bladder pathologies, but the significance of their expression in normal, healthy bile is not understood. We hypothesized that the MMP in bile may aid the digestion of native collagens that are resistant to conventional gastric proteases. Hence, the objective of this study was to characterize the bile MMP and check its regulation in association with dietary factors. We used substrate zymography, azocoll protease assay, and gelatin affinity chromatography to identify and purify the MMP from chicken bile. Using zymography and SDS PAGE, 5 bands at 70, 64, 58, 50, and 42 kDa were detected. The bands corresponding to 64, 50, and 42 kDa were identified as MMP2 using trypsin in-gel digestion and matrix-assisted laser desorption time-of-flight mass spectrometry and peptide mass fingerprinting. Chickens fed diets containing gelatin supplements showed higher levels of MMP expression in the bile by both azocoll assay and zymography. We conclude that the bile MMP may be associated with the digestion of collagens and other extracellular matrix proteins in avian diets.
Topics: Animal Feed; Animals; Azo Compounds; Bile; Chickens; Chromatography, Affinity; Chromatography, Gel; Collagen; Diet; Dietary Supplements; Electrophoresis, Polyacrylamide Gel; Male; Mass Spectrometry; Matrix Metalloproteinases; Random Allocation
PubMed: 24879699
DOI: 10.3382/ps.2013-03848 -
Gut May 1990
Review
Topics: Bile; Biliary Dyskinesia; Biliary Tract; Cholecystokinin; Cholelithiasis; Cholestasis; Humans; Middle Aged; Muscle Contraction
PubMed: 2190869
DOI: 10.1136/gut.31.5.571 -
Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR.Hepatology Communications Apr 2024Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile...
BACKGROUND
Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation.
METHODS
N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery.
RESULTS
MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts.
CONCLUSIONS
MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.
Topics: Humans; Bile; Bile Acids and Salts; Liver; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Receptors, G-Protein-Coupled
PubMed: 38517202
DOI: 10.1097/HC9.0000000000000383