Extracellular NAD+ response to post-hepatectomy liver failure: bridging preclinical and clinical findings

• Published in: Communications biology Vol. 7; no. 1; pp. 991 - 13
• Main Authors: Kamali, Can, Brunnbauer, Philipp, Kamali, Kaan, Saqr, Al-Hussein Ahmed, Arnold, Alexander, Harman Kamali, Gulcin, Babigian, Julia, Keshi, Eriselda, Mohr, Raphael, Felsenstein, Matthäus, Moosburner, Simon, Hillebrandt, Karl-Herbert, Bartels, Jasmin, Sauer, Igor Maximilian, Tacke, Frank, Schmelzle, Moritz, Pratschke, Johann, Krenzien, Felix
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/105; 13/106; 13/51; 14/34; 14/63; 64/60; 692/308/575; 692/4020/4021/1607/1604; Aged; Animals; Aspartate transaminase; Bilirubin; Biomedical and Life Sciences; Biosynthesis; Cell death; Cirrhosis; Disease Models, Animal; Enzymes; Female; Fibrosis; Hepatectomy; Hepatocytes; Hepatocytes - metabolism; Humans; Life Sciences; Liver cancer; Liver cirrhosis; Liver Cirrhosis - metabolism; Liver Cirrhosis - surgery; Liver diseases; Liver Failure - etiology; Liver Failure - metabolism; Liver Failure - pathology; Liver Failure - surgery; Male; Mice; Mice, Inbred C57BL; Middle Aged; NAD; NAD - metabolism; Nicotinamide phosphoribosyltransferase; Patients; Phosphoribosyltransferase; Risk factors; Spheroids; Transaminase; Viability
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06661-0

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.