Nutritional targeting circulating eNAMPT attenuates NLRP3 inflammasome activation in alcoholic liver injury: therapeutic potential of nicotinamide riboside

Abstract

Alcoholic liver disease (ALD) remains a major global health burden with limited effective nutritional strategies. We previously identified brown adipose tissue-derived extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a pathogenic factor in ALD, but the underlying mechanisms remained unclear. Here, we explored the role of eNAMPT on liver inflammation and evaluate the therapeutic potential of nicotinamide riboside (NR), a form of vitamin B3, as a potential nutritional intervention. We found that ethanol exposure significantly increased eNAMPT secretion from brown adipocytes (BACs) and elevated circulating eNAMPT levels in mice fed a chronic-plus-binge ethanol diet. RNA-seq analysis and rescue experiments showed that neutralizing eNAMPT reduced hepatic NLRP3 inflammasome activation and proinflammatory cytokine expression. In the co-culture experiment, BACs-derived eNAMPT induced NLRP3 inflammasome activation in hepatocytes and macrophages. However, this effect was abolished when eNAMPT was depleted from the conditioned medium of BACs. Furthermore, recombinant eNAMPT exerts a dose-dependent effect on the activation of the NLRP3 inflammasome in hepatocytes and macrophages. Importantly, oral supplementation with NR effectively suppressed ethanol-induced eNAMPT secretion and mitigated hepatic NLRP3 activation both in vivo and in vitro. The secretion of eNAMPT was inhibited when NAMPT was knocked down in BACs, thereby attenuating the anti-inflammatory effect of NR, indicating its protective effect is dependent on targeting eNAMPT secretion. Our findings reveal BACs-derived eNAMPT as a key mediator linking adipose–liver inflammation in ALD and support dietary NR as a promising intervention strategy by targeting eNAMPT.