Loss of claudin-3 impairs hepatic metabolism, biliary barrier function and cell proliferation in the murine liver.

Baier, Felix Alexander; Sánchez-Taltavull, Daniel; Yarahmadov, Tural; Castellà, Cristina Gómez; Jebbawi, Fadi; Keogh, Adrian; Tombolini, Riccardo; Odriozola, Adolfo; Castro Dias, Mariana; Deutsch, Urban; Furuse, Mikio; Engelhardt, Britta; Zuber, Benoît; Odermatt, Alex; Candinas, Daniel; Keogh-Stroka, Deborah M. (2021). Loss of claudin-3 impairs hepatic metabolism, biliary barrier function and cell proliferation in the murine liver. (In Press). Cellular and molecular gastroenterology and hepatology Elsevier 10.1016/j.jcmgh.2021.04.003

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BACKGROUND & AIMS

Tight junctions in the liver are essential to maintain the blood-biliary-barrier, however the functional contribution of individual tight junction proteins to barrier- and metabolic homeostasis remains largely unexplored. Here, we describe the cell type specific expression of tight junction genes in the murine liver, and explore the regulation and functional importance of the transmembrane protein claudin-3 in liver metabolism, barrier function and cell proliferation.

METHODS

The cell type specific expression of hepatic tight junction genes is described using our mouse liver single cell sequencing dataset. Differential gene expression in Cldn3-/- and Cldn3+/+ livers was assessed in young and aged mice by RNA-seq and hepatic tissue was analysed for lipid content and bile acid composition. A surgical model of partial hepatectomy (PHx) was used to induce liver cell proliferation.

RESULTS

Claudin-3 is a highly expressed tight junction protein found in the liver and is expressed predominantly in hepatocytes and cholangiocytes. The histology of Cldn3-/- livers showed no overt phenotype, and the canalicular tight junctions appeared intact. Nevertheless, by RNAseq we detected a downregulation of metabolic pathways in the livers of Cldn3-/- young and aged mice as well as a decrease in lipid content and a weakened biliary-barrier for primary bile acids, such as TCA, TCDCA and TMCA. Coinciding with defects in the biliary barrier and lower lipid metabolism, there was a diminished hepatocyte proliferative response in Cldn3-/- mice following PHx.

CONCLUSION

Our data shows that in the liver, claudin-3 is necessary to maintain metabolic homeostasis, retention of bile acids, and optimal hepatocyte proliferation during liver regeneration.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Baier, Felix Alexander; Sánchez Taltavull, Daniel; Yarahmadov, Tural; Keogh, Adrian; Tombolini, Riccardo; Odriozola Quesada, Adolfo; Mota Castro Dias, Mariana; Deutsch, Urban; Engelhardt, Britta; Zuber, Benoît; Candinas, Daniel and Keogh-Stroka, Deborah M.

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2352-345X

Publisher:

Elsevier

Language:

English

Submitter:

Cindy Carolyn Alpinice Schumacher

Date Deposited:

10 May 2021 09:53

Last Modified:

10 May 2021 10:02

Publisher DOI:

10.1016/j.jcmgh.2021.04.003

PubMed ID:

33866021

Uncontrolled Keywords:

bile acid claudin liver regeneration single cell RNA sequencing tight junction

BORIS DOI:

10.48350/156096

URI:

https://boris.unibe.ch/id/eprint/156096

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