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

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.

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice

“…71 In this study, significantly elevated KYNU and KMO levels after HFPO-DA exposure may be a result of AHR inhibition induced by decreased KA levels and at the same time can also be a result of metabolic shift in the Kyn pathway moving away from KA synthesis toward NAD synthesis (Figure 3E). An opposite metabolic shift from 3-HAA and QA to KA synthesis in hepatic ischemia-reperfusion (IR) injury was reported previously, 74 and the most possible reason for this reverse in metabolic direction might be the activation of PPARα, as PPARα agonists can alleviate apoptosis and autophagy in hepatic IR injury. 75 Yue et al have demonstrated that PPARα agonist Wy-14,643 can increase hepatic NAD and NAD/NADH ratio in mice by enhancing expression of proteins in the nicotinamide-NAD pathway, 68 thus the elevated NAD and NAD/NADH ratio in the present study may be due to activation of PPARα by HFPO-DA.…”

Impact of the delay in cryopreservation timing during biobanking procedures on human liver tissue metabolomics

“…Numerous cellular pathways have also been shown to be altered under ischemic conditions, which in turn influence the metabolic composition and activity of tissues [ 12 , 31 – 34 ]. In the liver, ischemia has been shown to induce anaerobic glycolysis, impaired mitochondrial respiration, inflammation-promoting perturbations of lipid metabolism, as well as alterations in the tryptophan-metabolizing kynurenine pathway [ 35 , 36 ]. Ischemia broadly represses oxidative metabolism of various intermediates, including fatty acids, carbohydrates, and amino acids [ 37 ].…”

β-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice

“…The raised expression of NAMPT, involving in the NAD + salvage pathway as the rate-limiting enzyme, and indole-2,3-dioxygenase 1 (IDO1), mediating NAD + de novo synthesis pathways, which might be required for the maintenance of depleted NAD+ and to supply the production of pro-inflammatory factors in sepsis. The supplementation of NAD + precursor could restore the overexpression of genes involved in these pathways, also affect the tryptophan and kynurenine metabolic pathways during NAD + de novo synthesis, and improve cellular immunomodulatory capacity [ 30 , 70 , 71 ]. Poly-adenosine diphosphate-ribose polymerases (PARPs) is a nuclear chromatin-associated protein, which function as an enzyme, could catalyze the transfer of ADP-ribose units from its substrate NAD + covalently to itself and other nuclear chromatin-associated proteins.…”