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

Autor: Bowen Xu, Peng Zhang, Xiaolong Tang, Shiguan Wang, Jing Shen, Yuanwen Zheng, Chao Gao, Ping Mi, Cuijuan Zhang, Hui Qu, Shiyang Li, Detian Yuan
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Advanced Science, Vol 9, Iss 35, Pp n/a-n/a (2022)
Druh dokumentu: article
ISSN: 2198-3844
DOI: 10.1002/advs.202204697
Popis: 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.
Databáze: Directory of Open Access Journals
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