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Advanced Science

Advanced Science

IF: 14.3
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Metabolic Rewiring of Kynurenine Pathway during Hepatic Ischemia–Reperfusion Injury Exacerbates Liver Damage by Impairing NAD Homeostasis

Published:30 October 2022 DOI: 10.1002/advs.202204697 PMID: 36310151
Bowen Xu, Peng Zhang, Xiaolong Tang, Shiguan Wang, Jing Shen, Yuanwen Zheng, Chao Gao, Ping Mi, Cuijuan Zhang, Hui Qu, Shiyang Li, Detian Yuan

Abstract

Hepatic ischemia–reperfusion (IR) injury remains a common issue lacking effective strategy and validated pharmacological targets. Here, using an unbiased metabolomics screen, this study finds that following murine hepatic IR, liver 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) decline while kynurenine and kynurenic acid (KYNA) increase. Kynurenine aminotransferases 2, functioning at the key branching point of the kynurenine pathway (KP), is markedly upregulated in hepatocytes during ischemia, shifting the kynurenine metabolic route from 3-HAA and QA to KYNA synthesis. Defects in QA synthesis impair de novo nicotinamide adenine dinucleotide (NAD) biosynthesis, rendering the hepatocytes relying on the salvage pathway for maintenance of NAD and cellular antioxidant defense. Blocking the salvage pathway following IR by the nicotinamide phosphoribosyltransferase inhibitor FK866 exacerbates liver oxidative damage and enhanced IR susceptibility, which can be rescued by the lipid peroxidation inhibitor Liproxstatin-1. Notably, nicotinamide mononucleotide administration once following IR effectively boosts NAD and attenuated IR-induced oxidative stress, inflammation, and cell death in the murine model. Collectively, the findings reveal that metabolic rewiring of the KP partitions it away from NAD synthesis in hepatic IR pathophysiology, and provide proof of concept that NAD augmentation is a promising therapeutic measure for IR-induced liver injury.

Substances (24)

Materials
Procduct Name CAS Molecular Formula Supplier Price
β-Nicotinamide Mononucleotide 1094-61-7 C11H15N2O8P 1011 suppliers $7.00-$2194.50
β-Nicotinamide Mononucleotide 1094-61-7 C11H15N2O8P 1011 suppliers $7.00-$2194.50
β-Nicotinamide Mononucleotide 1094-61-7 C11H15N2O8P 1011 suppliers $7.00-$2194.50
β-Nicotinamide Mononucleotide 1094-61-7 C11H15N2O8P 1011 suppliers $7.00-$2194.50
(E)-N-[4-(1-BENZOYL-PIPERIDIN-4-YL)-BUTYL]-3-PYRIDIN-3-YL-ACRYLAMIDE 658084-64-1 C24H29N3O2 174 suppliers $17.00-$2841.00
(E)-N-[4-(1-BENZOYL-PIPERIDIN-4-YL)-BUTYL]-3-PYRIDIN-3-YL-ACRYLAMIDE 658084-64-1 C24H29N3O2 174 suppliers $17.00-$2841.00
(E)-N-[4-(1-BENZOYL-PIPERIDIN-4-YL)-BUTYL]-3-PYRIDIN-3-YL-ACRYLAMIDE 658084-64-1 C24H29N3O2 174 suppliers $17.00-$2841.00
(E)-N-[4-(1-BENZOYL-PIPERIDIN-4-YL)-BUTYL]-3-PYRIDIN-3-YL-ACRYLAMIDE 658084-64-1 C24H29N3O2 174 suppliers $17.00-$2841.00
FK866 hydrochloride hydrate 658084-64-1 C24H29N3O2 1 suppliers $60.00-$390.00
FK866 hydrochloride hydrate 658084-64-1 C24H29N3O2 1 suppliers $60.00-$390.00

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