Extracellular NAD+ response to post-hepatectomy liver failure: bridging preclinical and clinical findings
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,...
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Published in | Communications biology Vol. 7; no. 1; pp. 991 - 13 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
14.08.2024
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2399-3642 2399-3642 |
DOI: | 10.1038/s42003-024-06661-0 |