Yang Xinxin, Zheng Endian, Lin Yuxian, Sun Haoyue, Zhang Ji, Yu Yingcong
Department of Infectious Diseases, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, 325000, Zhejiang, China.
Department of Gastroenterology, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, 325000, Zhejiang, China.
Hereditas. 2025 Aug 16;162(1):161. doi: 10.1186/s41065-025-00529-x.
Alcoholism is a significant contributor to the development of alcoholic liver disease, for which no universally accepted and effective treatment currently exists. A precursor of NAD, β-Nicotinamide mononucleotide (NMN), has revealed potential therapeutic benefits. However, its effectiveness in preventing ethanol-induced liver damage remains uncertain.
The objective of this study was to assess the protective effects of NMN and elucidate its potential mechanisms using a mouse model subjected to chronic and binge ethanol feeding. Eight-week-old C57BL/6J mice were randomly assigned to one of four groups (n = 10 per group): control (CTRL), ethanol (EtOH), ethanol with low-dose NMN (EtOH + NMN(L)), and ethanol with high-dose NMN (EtOH + NMN(H)). Following the completion of the experimental protocol, the mice were euthanized at designated time points, and blood, liver, and ileum tissues were collected for analysis of relevant biomarkers.
Compared to the CTRL group, the EtOH group demonstrated increased liver specific gravity and elevated blood ALT levels. Administration of NMN improved histopathological changes in the liver and ileum of the mice. NMN significantly counteracted the ethanol-induced elevation in liver MDA levels and restored the diminished glutathione (GSH) and superoxide dismutase (SOD) activity levels caused by ethanol exposure. Additionally, NMN inhibited the ethanol-induced expression of cytochrome P450 2E1 (CYP2E1). It also reduced the release of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which were triggered by ethanol exposure, improved energy homeostasis in the ileum, and reversed the downregulation of mRNA and protein expression of key tight junction proteins in the ileum, specifically ZO-1, Claudin-1, and Occludin, thereby restoring their functional integrity. Furthermore, NMN activated the NAD/ SIRT1 signaling pathway, leading to the upregulation of all target genes.
NMN supplementation provides protection against alcoholic liver injury in a mouse model, potentially through the upregulation of the cellular NAD/ SIRT1 pathway. This upregulation enhances antioxidant and anti-inflammatory activities and improves intestinal permeability.
酒精中毒是酒精性肝病发展的一个重要因素，目前尚无普遍接受且有效的治疗方法。烟酰胺腺嘌呤二核苷酸（NAD）的前体β-烟酰胺单核苷酸（NMN）已显示出潜在的治疗益处。然而，其预防乙醇诱导的肝损伤的有效性仍不确定。
本研究的目的是使用慢性和暴饮乙醇喂养的小鼠模型评估NMN的保护作用并阐明其潜在机制。将8周龄的C57BL/6J小鼠随机分为四组之一（每组n = 10）：对照组（CTRL）、乙醇组（EtOH）、低剂量NMN乙醇组（EtOH + NMN(L)）和高剂量NMN乙醇组（EtOH + NMN(H)）。实验方案完成后，在指定时间点对小鼠实施安乐死，并收集血液、肝脏和回肠组织以分析相关生物标志物。
与CTRL组相比，EtOH组肝脏比重增加，血液谷丙转氨酶（ALT）水平升高。给予NMN改善了小鼠肝脏和回肠的组织病理学变化。NMN显著抵消了乙醇诱导的肝脏丙二醛（MDA）水平升高，并恢复了因乙醇暴露而降低的谷胱甘肽（GSH）和超氧化物歧化酶（SOD）活性水平。此外，NMN抑制了乙醇诱导的细胞色素P450 2E1（CYP2E1）的表达。它还减少了由乙醇暴露引发的促炎细胞因子的释放，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β），改善了回肠的能量稳态，并逆转了回肠中关键紧密连接蛋白（特别是闭合蛋白-1（ZO-1）、闭合蛋白-1（Claudin-1）和闭合蛋白（Occludin））mRNA和蛋白表达的下调，从而恢复了它们的功能完整性。此外，NMN激活了NAD/沉默信息调节因子1（SIRT1）信号通路，导致所有靶基因上调。
补充NMN可在小鼠模型中预防酒精性肝损伤，可能是通过上调细胞NAD/SIRT1途径实现的。这种上调增强了抗氧化和抗炎活性，并改善了肠道通透性。
