scholarly journals The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO3- Umbrella': An Integrated Line of Defense against Toxic Bile Acids

2015 ◽  
Vol 33 (3) ◽  
pp. 397-407 ◽  
Author(s):  
Lucas J. Maillette de Buy Wenniger ◽  
Simon Hohenester ◽  
Luca Maroni ◽  
Sandra J. van Vliet ◽  
Ronald P. Oude Elferink ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Protective Layer ◽  
Enzymatic Digestion ◽  
Biliary Cirrhosis ◽  
Membrane Glycoproteins ◽  
Neuraminidase Treatment ◽  
Protective Function ◽  
Membrane Bound ◽  
Acid Toxicity

Background: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a ‘biliary HCO3- umbrella', i.e. apical cholangiocellular HCO3- secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the ‘biliary HCO3- umbrella' and thus preventing cholangiotoxicity of bile acids. Key Messages: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pKa ≥4), but not taurochenodeoxycholate (pKa <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. Conclusion: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the ‘biliary HCO3- umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity.

scholarly journals Recent advances in understanding bile acid homeostasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2029 ◽  
Author(s):  
John YL Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Recent Advances ◽  
Bile Acid Pool Size ◽  
Bile Acid Receptor ◽  
Acid Toxicity ◽  
G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

scholarly journals Bile Acid Signaling in Neurodegenerative and Neurological Disorders

2020 ◽  
Vol 21 (17) ◽  
pp. 5982
Author(s):  
Stephanie M. Grant ◽  
Sharon DeMorrow
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Neurological Diseases ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Membrane Bound ◽  
Bile Acid Receptors ◽  
Cholestatic Diseases

Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.

scholarly journals Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in the abcb11−/− mouse: transport and gene expression studies

2013 ◽  
Vol 305 (4) ◽  
pp. G286-G294 ◽  
Author(s):  
Renxue Wang ◽  
Lin Liu ◽  
Jonathan A. Sheps ◽  
Dana Forrest ◽  
Alan F. Hofmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Bile Acids ◽  
Bile Flow ◽  
Biliary Cirrhosis ◽  
Beneficial Effects ◽  
Elevated Liver Enzymes ◽  
Genes Encoding ◽  
End Stage

The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice ( abcb11 −/−) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11−/− mice. Feeding UDCA to abcb11−/− mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11−/− mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11−/− mice. UDCA fed to abcb11−/− mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11−/− mice.

Downregulation of a human colonic sialyltransferase by a secondary bile acid and a phorbol ester

1998 ◽  
Vol 274 (3) ◽  
pp. G599-G606 ◽  
Author(s):  
Ming Li ◽  
Ravi Vemulapalli ◽  
Asad Ullah ◽  
Leighton Izu ◽  
Michael E. Duffey ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Phorbol Ester ◽  
Cancer Cell Line ◽  
Colon Cancer Cell Line ◽  
Mrna Levels ◽  
Membrane Glycoproteins ◽  
Secondary Bile Acid ◽  
Colonic Cells

Fecal constituents such as bile acids and increased sialylation of membrane glycoproteins by α-2,6-sialyltransferase (HST6N-1) may contribute to colorectal tumorigenesis. We hypothesized that bile acids and phorbol ester [12- O-tetradecanoylphorbol-13-acetate (TPA)] would upregulate HST6N-1 in colonic cells. However, deoxycholate (DOC) (300 μmol/l), a secondary bile acid, and TPA (20 ng/ml) decreased expression of an ∼100-kDa glycoprotein bearing α-2,6-linked sialic acid in a colon cancer cell line (T84) in vitro. HST6N-1 mRNA levels were reduced ∼80% by treatment (≤24 h) with DOC or TPA but not by cholate, a primary bile acid. Treatment (24 h) with DOC or TPA decreased activity of this enzyme to 30% and 13% of control, respectively. These effects of DOC and TPA were transcriptional and were mediated by Ca2+ and protein kinase C, respectively. Thus DOC and TPA both downregulated, and did not upregulate, α-2,6-sialyltransferase expression in vitro, but by different transduction pathways. As colorectal tumors grow, their progressive removal from the fecal milieu that normally downregulates this enzyme may favor invasion and metastasis.

scholarly journals Glyceric Prodrug of Ursodeoxycholic Acid (UDCA): Novozym 435-Catalyzed Synthesis of UDCA-Monoglyceride

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5966
Author(s):  
Federico Zappaterra ◽  
Stefania Costa ◽  
Daniela Summa ◽  
Bruno Semeraro ◽  
Virginia Cristofori ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Bile Acids ◽  
Immobilized Lipase ◽  
Critical Role ◽  
Clinical Effectiveness ◽  
Water Soluble ◽  
Novozym 435 ◽  
Biliary Cirrhosis ◽  
Enzymatic Esterification

Bile acids (BAs) are a family of steroids synthesized from cholesterol in the liver. Among bile acids, ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. The clinical effectiveness of UDCA includes its choleretic activity, the capability to inhibit hydrophobic bile acid absorption by the intestine under cholestatic conditions, reducing cholangiocyte injury, stimulation of impaired biliary output, and inhibition of hepatocyte apoptosis. Despite its clinical effectiveness, UDCA is poorly soluble in the gastro-duodeno-jejunal contents, and pharmacological doses of UDCA are not readily soluble in the stomach and intestine, resulting in incomplete absorption. Indeed, the solubility of 20 mg/L greatly limits the bioavailability of UDCA. Since the bioavailability of drug products plays a critical role in the design of oral administration dosages, we investigated the enzymatic esterification of UDCA as a strategy of hydrophilization. Therefore, we decided to enzymatically synthesize a glyceric ester of UDCA bile acid to produce a more water-soluble molecule. The esterification reactions between UDCA and glycerol were performed with an immobilized lipase B from Candida antarctica (Novozym 435) in solvent-free and solvent-assisted systems. The characterization of the UDCA-monoglyceride, enzymatically synthesized, has been performed by 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, IR, and MS spectroscopy.

The Role of FXR in Disorders of Bile Acid Homeostasis

Physiology ◽  
2008 ◽  
Vol 23 (5) ◽  
pp. 286-295 ◽  
Author(s):  
Jyrki J. Eloranta ◽  
Gerd A. Kullak-Ublick
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Nuclear Receptor ◽  
Genetic Variants ◽  
Target Genes ◽  
Acid Toxicity

As ligands for the nuclear receptor FXR, bile acids regulate their own synthesis, transport, and conjugation, thus protecting against bile acid toxicity. Recently, the role of genetic variants in FXR itself, FXR target genes, and regulators of FXR in the pathophysiology of the liver and intestine has become increasingly evident.

scholarly journals Bile Acids as Hormones: The FXR-FGF15/19 Pathway

2015 ◽  
Vol 33 (3) ◽  
pp. 327-331 ◽  
Author(s):  
Steven A. Kliewer ◽  
David J. Mangelsdorf
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Cell Surface Receptor ◽  
Biliary Cirrhosis ◽  
Receptor Complex ◽  
Surface Receptor ◽  
A Cell

While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.

Sign in / Sign up

Export Citation Format

Share Document