Mapping early serum proteome signatures of liver regeneration in living donor liver transplant cases

Author:

Carmona‐Rodríguez Lorena1ORCID,Gajadhar Aaron S.2,Blázquez‐García Irene1,Guerrero Laura1,Fernández‐Rojo Manuel A.34ORCID,Uriarte Iker567ORCID,Mamani‐Huanca Maricruz8ORCID,López‐Gonzálvez Ángeles8ORCID,Ciordia Sergio1,Ramos Antonio9,Herrero José Ignacio6710ORCID,Fernández‐Barrena Maite G.567,Arechederra María567,Berasain Carmen567,Quiroga Jorge6710,Sangro Bruno6710,Argemi Josepmaría6710,Pardo Fernando6710,Rotellar Fernando6710,López Daniel2,Barbas Coral8ORCID,Ávila Matías A.567,Corrales Fernando J.1ORCID

Affiliation:

1. Functional Proteomics Laboratory Centro Nacional de Biotecnología (CSIC) Madrid Spain

2. Thermo Fisher Scientific San Jose California USA

3. Hepatic Regenerative Medicine Laboratory Madrid Institute for Advanced Studies in Food Madrid Spain

4. School of Medicine The University of Queensland Brisbane Queensland Australia

5. Proteobotics SL Madrid Spain

6. CIMA, Universidad de Navarra Pamplona Spain

7. Clínica Universidad de Navarra Pamplona Spain

8. CIBERehd, Instituto de Salud Carlos III Madrid Spain

9. Instituto de Investigaciones Sanitarias de Navarra‐IdiSNA Pamplona Spain

10. Centre for Metabolomics and Bioanalysis (CEMBIO) Universidad San Pablo‐CEU, CEU Universities, Urbanización Montepríncipe Madrid Spain

Abstract

AbstractThe liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR‐FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14‐3‐3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow‐up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.

Funder

CSIC

Publisher

Wiley

Subject

Clinical Biochemistry,Molecular Medicine,General Medicine,Biochemistry

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