Elevated Epithelial Splicing Regulatory Protein 1 Expression in Biliary Atresia Indicates Its Potential as a Molecular Marker

Biomolecules, vol. 16, pp. 9

Abstract

Cholangiopathies encompass a wide range of chronic liver diseases that target biliary epithelial cells, leading to significant morbidity and mortality due to their progressive nature, limited treatment options, and complex clinical management. Currently, clinically validated biomarkers capable of distinguishing obstructive cholangiopathies, such as biliary atresia (BA), from other cholangiopathies are lacking, hindering timely intervention. RNA-binding proteins (RBPs) have been increasingly linked to human diseases but their roles in cholangiopathies remain underexplored. We assessed the expression of the RBP epithelial splicing regulatory protein 1 (ESRP1) in murine models of cholangiopathies and in the human system. Our findings demonstrate that ESRP1 is highly and specifically expressed in cholestatic liver injury models, including bile duct-ligated, diethoxycarboncyl-1,4-dihydrocollidine-treated, and Mdr2−/− mice when compared with other liver injury models. Importantly, ESRP1 is markedly elevated in the livers of patients with BA and cystic fibrosis-related liver disease, localizing to cholangiocytes and peri-biliary hepatic cells, but is minimal in primary sclerosing cholangitis and primary biliary cholangitis. Moreover, patient-derived BA organoids and biliatresone-treated healthy organoids also display ESRP1 expression. Bioinformatics analysis further implicates ESRP1 in key cholangiopathy-associated pathways, warranting deeper mechanistic investigation. Thus, ESRP1 holds potential as a molecular marker for obstructive cholangiopathies, warranting further mechanistic studies.

Authors 13

1. Giorgia Ammirata

   University of Turin

   Affiliation as printed

   Molecular Biotechnology Center “Guido Tarone”, University of Turin, 10126 Turin, Italy

   Molecular Biotechnology Center "Guido Tarone", University of Turin, 10126 Turin, Italy

2. Victor Navarro‐Tableros

   University of Turin

   Affiliation as printed

   2i3T-Incubatore di Imprese, University of Turin, 10126 Turin, Italy

   Molecular Biotechnology Center “Guido Tarone”, University of Turin, 10126 Turin, Italy

   Molecular Biotechnology Center "Guido Tarone", University of Turin, 10126 Turin, Italy

3. Marta Manco

   University of Turin

   Affiliation as printed

   Molecular Biotechnology Center “Guido Tarone”, University of Turin, 10126 Turin, Italy

   Molecular Biotechnology Center "Guido Tarone", University of Turin, 10126 Turin, Italy

4. Luigi Chiusa

   Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · University of Turin

   Affiliation as printed

   Pathology Unit, Department of Medical Sciences, University of Turin and AOU Città Della Salute e Della Scienza, 10126 Turin, Italy

5. Alice Ponte

   Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · Ospedale Regina Margherita

   Affiliation as printed

   Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, AOU Città Della Salute e Della Scienza di Torino, 10126 Turin, Italy

6. Michele Pinon

   Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · Ospedale Regina Margherita

   Affiliation as printed

   Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, AOU Città Della Salute e Della Scienza di Torino, 10126 Turin, Italy

7. Renato Romagnoli

   Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · University of Turin

   Affiliation as printed

   Liver Transplant Center, Department of Surgical Sciences, University of Turin and AOU Città Della Salute e Della Scienza, 10126 Turin, Italy

8. Ralf Weiskirchen Aachen Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC)

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany

9. Paola Cassoni

   Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · University of Turin

   Affiliation as printed

   Pathology Unit, Department of Medical Sciences, University of Turin and AOU Città Della Salute e Della Scienza, 10126 Turin, Italy

10. Pier Luigi Calvo

    Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · Ospedale Regina Margherita

    Affiliation as printed

    Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, AOU Città Della Salute e Della Scienza di Torino, 10126 Turin, Italy

11. Ugo Ala

    University of Turin

    Affiliation as printed

    Department of Veterinary Sciences, University of Turin, Grugliasco, 10095 Turin, Italy

12. Fiorella Altruda

    University of Turin

    Affiliation as printed

    Molecular Biotechnology Center “Guido Tarone”, University of Turin, 10126 Turin, Italy

    Molecular Biotechnology Center "Guido Tarone", University of Turin, 10126 Turin, Italy

13. Sharmila Fagoonee corresponding

    Institute of Biostructure and Bioimaging · National Research Council · University of Turin

    Affiliation as printed

    Institute of Biostructure and Bioimaging (CNR), 10126 Turin, Italy

    Molecular Biotechnology Center “Guido Tarone”, University of Turin, 10126 Turin, Italy

    Molecular Biotechnology Center "Guido Tarone", University of Turin, 10126 Turin, Italy