Abstract

Liver fibrosis progressing to cirrhosis is a major risk factor for liver cancer, impacting surgical treatment and survival. Our study focuses on the role of extracellular nicotinamide adenine dinucleotide (eNAD+) in liver fibrosis, analyzing liver disease patients undergoing surgery. Additionally, we explore NAD+’s therapeutic potential in a mouse model of extended liver resection and in vitro using 3D hepatocyte spheroids. eNAD+ correlated with aspartate transaminase (AST) and bilirubin after liver resection (AST: r = 0.2828, p = 0.0087; Bilirubin: r = 0.2584, p = 0.0176). Concordantly, post-hepatectomy liver failure (PHLF) was associated with higher eNAD+ peaks (n = 10; p = 0.0063). Post-operative eNAD+ levels decreased significantly (p < 0.05), but in advanced stages of liver fibrosis or cirrhosis, this decline not only diminished but actually showed a trend towards an increase. The expression of NAD+ biosynthesis rate-limiting enzymes, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), were upregulated significantly in the liver tissue of patients with higher liver fibrosis stages (p < 0.0001). Finally, the administration of NAD+ in a 3D hepatocyte spheroid model rescued hepatocytes from TNFalpha-induced cell death and improved viability (p < 0.0001). In a mouse model of extended liver resection, NAD+ treatment significantly improved survival (p = 0.0158) and liver regeneration (p = 0.0186). Our findings reveal that eNAD+ was upregulated in PHLF, and rate-limiting enzymes of NAD+ biosynthesis demonstrated higher expressions under liver fibrosis. Further, eNAD+ administration improved survival after extended liver resection in mice and enhanced hepatocyte viability in vitro. These insights may offer a potential target for future therapies.

An analysis on liver disease patients suggests that extracellular Nicotinamide adenine dinucleotide (eNAD + ) correlates with liver fibrosis and post-hepatectomy liver failure, with NAD+ administration improving survival and liver regeneration in mice and hepatocyte viability in vitro.

Details

Title
Extracellular NAD+ response to post-hepatectomy liver failure: bridging preclinical and clinical findings
Author
Kamali, Can 1   VIAFID ORCID Logo  ; Brunnbauer, Philipp 1 ; Kamali, Kaan 1 ; Saqr, Al-Hussein Ahmed 1 ; Arnold, Alexander 2 ; Harman Kamali, Gulcin 3   VIAFID ORCID Logo  ; Babigian, Julia 1 ; Keshi, Eriselda 4 ; Mohr, Raphael 5   VIAFID ORCID Logo  ; Felsenstein, Matthäus 4 ; Moosburner, Simon 4 ; Hillebrandt, Karl-Herbert 4 ; Bartels, Jasmin 1 ; Sauer, Igor Maximilian 1   VIAFID ORCID Logo  ; Tacke, Frank 5   VIAFID ORCID Logo  ; Schmelzle, Moritz 6 ; Pratschke, Johann 1 ; Krenzien, Felix 7   VIAFID ORCID Logo 

 Augustenburger Platz 1, Charité – Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Surgery - Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639) 
 Charitéplatz 1, Charité – Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639) 
 Department of Pathology, University of Health Sciences, Prof. Dr. Cemil Taşçıoğlu City Hospital, Istanbul, Turkey (GRID:grid.506076.2) (ISNI:0000 0004 1797 5496) 
 Augustenburger Platz 1, Charité – Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Surgery - Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639); Charitéplatz 1, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, Berlin, Germany (GRID:grid.484013.a) 
 Augustenburger Platz 1, Charité – Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology - Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
 Carl-Neuberg-Straße 1, Hannover Medical School, Department of General, Visceral and Transplant Surgery, Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877) 
 Augustenburger Platz 1, Charité – Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Surgery - Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639); Charitéplatz 1, Charité – Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639) 
Pages
991
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3092977370
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.