New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study

Iker Uriarte; Eva Santamaria; Amaya López-Pascual; María J Monte; Josepmaria Argemí; M Ujue Latasa; Elena Adán-Villaescusa; Ainara Irigaray; Jose M Herranz; María Arechederra; Jorge Basualdo; Felipe Lucena; Fernando J Corrales; Fernando Rotellar; Fernando Pardo; Gregory Merlen; Dominique Rainteau; Bruno Sangro; Thierry Tordjmann; Carmen Berasain; Jose J G Marín; Maite G Fernández-Barrena; Ignacio Herrero; Matias A Avila

doi:10.1016/j.bbadis.2024.167166

New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 19;1870(5):167166. doi: 10.1016/j.bbadis.2024.167166. Online ahead of print.

Authors

Iker Uriarte¹, Eva Santamaria¹, Amaya López-Pascual², María J Monte³, Josepmaria Argemí⁴, M Ujue Latasa², Elena Adán-Villaescusa⁵, Ainara Irigaray⁵, Jose M Herranz¹, María Arechederra⁶, Jorge Basualdo⁷, Felipe Lucena⁸, Fernando J Corrales⁹, Fernando Rotellar¹⁰, Fernando Pardo¹⁰, Gregory Merlen¹¹, Dominique Rainteau¹², Bruno Sangro⁴, Thierry Tordjmann¹¹, Carmen Berasain¹, Jose J G Marín¹³, Maite G Fernández-Barrena⁶, Ignacio Herrero¹⁴, Matias A Avila¹⁵

Affiliations

¹ Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
² Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
³ CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Université Paris-Saclay, Inserm U1193, Orsay, France.
⁴ CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain.
⁵ Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
⁶ Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
⁷ Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain; Internal Medicine Department, ICOT Hospital Ciudad de Telde, Las Palmas, Spain.
⁸ Internal Medicine Department, Navarra University Clinic, Pamplona, Spain.
⁹ Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain.
¹⁰ General Surgery Department, Navarra University Clinic, Pamplona, Spain.
¹¹ Université Paris-Saclay, Inserm U1193, Orsay, France.
¹² Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine, Paris, France.
¹³ CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.
¹⁴ CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain; Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain. Electronic address: iherrero@unav.es.
¹⁵ Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain. Electronic address: maavila@unav.es.

PMID: 38642480
DOI: 10.1016/j.bbadis.2024.167166

Abstract

Background and aims: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol.

Methods: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot.

Results: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet.

Conclusions: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.

Keywords: 7α-Hydroxy-4-cholesten-3-one (C4); Bile acids; CYP7A1; FGF19; Liver regeneration; Liver transplantation.