Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation
Marta Alonso-Peña,
Ricardo Espinosa-Escudero,
Heike M. Hermanns,
Oscar Briz,
Jose M. Herranz,
Carmen Garcia-Ruiz,
Jose C. Fernandez-Checa,
Javier Juamperez,
Matias Avila,
Josepmaria Argemi,
Ramon Bataller,
Javier Crespo,
Maria J. Monte,
Andreas Geier,
Elisa Herraez,
Jose J. G. Marin
Affiliations
Marta Alonso-Peña
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
Ricardo Espinosa-Escudero
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
Heike M. Hermanns
Division of Hepatology, Würzburg University Hospital, Medical Clinic II, 97080 Würzburg, Germany
Oscar Briz
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
Jose M. Herranz
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
Carmen Garcia-Ruiz
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
Jose C. Fernandez-Checa
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
Javier Juamperez
Pediatric Hepatology and Liver Transplantation Unit, Vall d’Hebron University Hospital (HVH), Universitat Autónoma de Barcelona, 08035 Barcelona, Spain
Matias Avila
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
Josepmaria Argemi
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
Ramon Bataller
Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Javier Crespo
Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39008 Santander, Spain
Maria J. Monte
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
Andreas Geier
Division of Hepatology, Würzburg University Hospital, Medical Clinic II, 97080 Würzburg, Germany
Elisa Herraez
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
Jose J. G. Marin
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4α (HNF4α) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7α-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4α levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile.
