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

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Author information

Affiliations

  • 1. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
      Authors
    • Uriarte I 1
    • Santamaria E 1
    • Herranz JM 1
    • Berasain C 1
    (4 authors)
  • 2. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
      Authors
    • López-Pascual A 2
    • Latasa MU 2
    (2 authors)
  • 3. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Université Paris-Saclay, Inserm U1193, Orsay, France.
      Authors
    • Monte MJ 3
    (1 author)
  • 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.
      Authors
    • Argemí J 4
    • Sangro B 4
    • Herrero I 4
    (3 authors)
  • 5. Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
      Authors
    • Adán-Villaescusa E 5
    • Irigaray A 5
    (2 authors)
    • Show all (13)

ORCIDs linked to this article

Biochimica et Biophysica acta. Molecular Basis of Disease, 19 Apr 2024, 1870(5):167166
https://doi.org/10.1016/j.bbadis.2024.167166 PMID: 38642480 

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.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/j.bbadis.2024.167166

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Funding 

Funders who supported this work.

España Ministerio de Ciencia Innovación y Universidades