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

doi:10.3390/cells11243983

Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation

Cells. 2022 Dec 9;11(24):3983. doi: 10.3390/cells11243983.

Authors

Marta Alonso-Peña^{1

2

3}, Ricardo Espinosa-Escudero¹, Heike M Hermanns³, Oscar Briz^{1

4}, Jose M Herranz^{4

5}, Carmen Garcia-Ruiz^{4

6

7}, Jose C Fernandez-Checa^{4

6

7}, Javier Juamperez⁸, Matias Avila^{4

5}, Josepmaria Argemi^{4

5

9}, Ramon Bataller⁹, Javier Crespo^{2

4}, Maria J Monte^{1

4}, Andreas Geier³, Elisa Herraez^{1

4}, Jose J G Marin^{1

4}

Affiliations

¹ Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain.
² Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39008 Santander, Spain.
³ Division of Hepatology, Würzburg University Hospital, Medical Clinic II, 97080 Würzburg, Germany.
⁴ Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain.
⁵ Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain.
⁶ Institute of Biomedical Research of Barcelona (IIBB), Centro Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain.
⁷ Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁸ Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital (HVH), Universitat Autónoma de Barcelona, 08035 Barcelona, Spain.
⁹ Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

Abstract

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.

Keywords: ACOX2; ASH; BAAT; NAFL; NASH; bile acid; inflammation; oncostatin M.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Acids and Salts*
Cholesterol / metabolism
Cytokines
Hepatitis*
Humans
Inflammation
Tandem Mass Spectrometry

Substances

Bile Acids and Salts
Cholesterol
Cytokines

Grants and funding

This study was supported by the CIBERehd (EHD15PI05/2016) and Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819, PI20/00189, and PI20/01663 co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”); Junta de Castilla y Leon (SA074P20); Fundació Marato TV3 (Ref. 201916/31), Spain; AECC Scientific Foundation (2017/2020), Spain; Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of Wuerzburg, Germany (Project A-E-384 to H.M.H.); grants PID2019-111669-RB-I00, PID2020-115055RB-I00 from Agencia Estatal de Investigación (AEI), Spain; the AGAUR of the Generalidad de Cataluña SGR-2017-1112, Spain; and European Cooperation in Science & Technology (COST) Action CA17112. R.E.E was recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). J.A. was recipient of a grant from Fundación Echebano (2020–2022).