glycodeoxycholic-acid and Cholestasis

Biliary atresia (BA) is a severe inflammatory and fibrosing neonatal cholangiopathy disease characterized by progressive obstruction of extrahepatic bile ducts, resulting in cholestasis and progressive hepatic failure. Cholestasis may play an important role in the inflammatory and fibrotic pathological processes, but its specific mechanism is still unclear. Necroptosis mediated by Z-DNA-binding protein 1 (ZBP1)/phosphorylated-mixed lineage kinase domain-like pseudokinase (p-MLKL) is a prominent pathogenic factor in inflammatory and fibrotic diseases, but its function in BA remains unclear. Here, we aim to determine the effect of macrophage necroptosis in the BA pathology, and to explore the specific molecular mechanism. We found that necroptosis existed in BA livers, which was occurred in liver macrophages. Furthermore, this process was mediated by ZBP1/p-MLKL, and the upregulated expression of ZBP1 in BA livers was correlated with liver fibrosis and prognosis. Similarly, in the bile duct ligation (BDL) induced mouse cholestatic liver injury model, macrophage necroptosis mediated by ZBP1/p-MLKL was also observed. In vitro, conjugated bile acid-glycodeoxycholate (GDCA) upregulated ZBP1 expression in mouse bone marrow-derived monocyte/macrophages (BMDMs) through sphingosine 1-phosphate receptor 2 (S1PR2), and the induction of ZBP1 was a prerequisite for the enhanced necroptosis. Finally, after selectively knocking down of macrophage S1pr2 in vivo, ZBP1/p-MLKL-mediated necroptosis was decreased, and further collagen deposition was markedly attenuated in BDL mice. Furthermore, macrophage Zbp1 or Mlkl specific knockdown also alleviated BDL-induced liver injury/fibrosis. In conclusion, GDCA/S1PR2/ZBP1/p-MLKL mediated macrophage necroptosis plays vital role in the pathogenesis of BA liver fibrosis, and targeting this process may represent a potential therapeutic strategy for BA.

Topics: Animals; Biliary Atresia; Cholestasis; Disease Models, Animal; Glycodeoxycholic Acid; Liver Cirrhosis; Macrophages; Mice; Necroptosis; Protein Kinases; RNA-Binding Proteins; Sphingosine-1-Phosphate Receptors

Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5-80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.

Topics: Acetaminophen; Adult; Biomarkers; Case-Control Studies; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Overdose; Female; Glycodeoxycholic Acid; Humans; Liver Function Tests; Male; Middle Aged; Predictive Value of Tests; Young Adult

To evaluate why hemolysis of red blood cells (RBC) by bile acids varies in different mammalian species, we determined the mean corpuscular volume (MCV), lipid content and the concentrations of the conjugates of deoxycholate and of NaCl inducing 50% hemolysis of RBC from healthy humans, pigs, horses, cows, sheep and jaundiced humans. A volume of 0.05 mL of washed RBC at 1% hematocrit, which has the same lipid content but different phospholipid composition and number of erythrocytes (owing to the variable MCV), was incubated in taurodeoxycholate (TDC) solution (0-5 mM) to determine the TDC concentration inducing 50% hemolysis (TDC50). The TDC50 was highest in RBC of sheep and decreased within the series sheep > pig > cow > horse > healthy human > jaundiced human, which have generally increasing MCV. The osmotic resistance followed an inverse order, with jaundiced human > healthy human > horse > cow > pig > sheep. Although we found no correlation between the TDC50 and phospholipid composition of the erythrocytes tested, the extent of bile salt-induced hemolysis seemed to depend on both the MCV and the number of erythrocytes in the incubation medium.

Topics: Animals; Bile Acids and Salts; Cholestasis; Dose-Response Relationship, Drug; Erythrocyte Membrane; Erythrocyte Volume; Glycodeoxycholic Acid; Hemolysis; Horses; Humans; Osmotic Fragility; Phospholipids; Ruminants; Sodium Chloride; Sphingomyelins; Taurodeoxycholic Acid

Systemic endotoxaemia is associated with postoperative renal dysfunction in obstructive jaundice, and can be prevented by the pre-operative administration of certain bile salts. In order to find the most effective bile salt for use in this condition, a comparison of the anti-endotoxic activities of different bile salts was performed. Bile salts were incubated in vitro with endotoxin and the resultant endotoxin level was measured with a quantitative limulus assay. The in vivo effects of different oral bile salts on the intestinal absorption of radiolabelled endotoxin from rats with obstructive jaundice were compared. The in vitro and in vivo anti-endotoxic activities of bile salts related to their known detergent activities. Deoxycholic acid and its conjugates were the most effective and should be the bile salts of choice for further clinical evaluation in obstructive jaundice in man.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; Cholic Acid; Cholic Acids; Deoxycholic Acid; Endotoxins; Escherichia coli; Glycodeoxycholic Acid; Intestinal Absorption; Male; Rats; Rats, Inbred Strains; Taurocholic Acid; Taurodeoxycholic Acid; Ursodeoxycholic Acid

Measurements of serum bile acids (glycine conjugates of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids) by radioimmunoassay in a variety of pediatric hepatobiliary disorders showed elevations in neonatal hepatitis syndromes, cholestasis, and hepatitis of extrahepatic or intrahepatic origin. Measurements of individual serum bile acids failed to differentiate between the various neonatal hepatitis syndromes. In one patient with cholestasis, the increased levels of bile acids observed returned to normal following therapy with cholestyramine and phenobarbital. In chronic active hepatitis the serum bile acid values correlated well with the bilirubin and SGOT in response to therapy with corticosteroids. These data confirm suggestions that serum cholylglycine and chenodeoxycholylglycine levels are a sensitive indicator of disturbed hepatic function and can be used in monitoring the course, activity, and therapeutic response in various hepatitis syndromes. In Reye's syndrome and protracted diarrhea of infancy, elevations in serum bile acids were detected without associated hyperbilirubinemia and provided additional evidence of disturbed hepatic function.

Topics: Adolescent; Bile Acids and Salts; Child; Child, Preschool; Cholestasis; Cystic Fibrosis; Diarrhea, Infantile; Glycochenodeoxycholic Acid; Glycocholic Acid; Glycodeoxycholic Acid; Hepatitis; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Intestinal Diseases; Liver Diseases; Reye Syndrome