Hepatic nicotinamide adenine dinucleotide (NAD+) reduction is a pathological hallmark and pathogenic basis for alcohol-associated liver disease (ALD). This study investigated the therapeutic role of nicotinamide mononucleotide (NMN), a NAD+ precursor naturally presenting in various dietary sources, against ALD. Here, we show that NMN supplementation attenuates NAD+ decline, which in turn attenuates hepatic lipid deposition, dysregulated lipid metabolism genes, oxidative stress, and inflammation in ALD mice, and ultimately ameliorated liver injury. Transcriptomics-based mechanistic analysis demonstrates that alcohol-reduced hepcidin antimicrobial peptide (Hamp) is rescued by NMN, alongside the recovery of circulatory and hepatic iron levels. The hepatic Hamp expression is positively associated with NAD+ content in the liver. Hamp knockdown significantly abolishes NMN-improved lipid accumulation and the dysregulation of lipid metabolism-related genes in ethanol-treated hepatocytes. Further analysis identifies a C/EBPα-involved transcriptional regulation mechanism in NMN-protected Hamp in ALD. These findings identify NMN as a promising dietary therapeutic for ALD, acting via the C/EBPα/Hamp signaling axis. Nicotinamide mononucleotide (NMN) restores hepatic NAD+, which promotes C/EBPα-mediated Hamp transcription, thereby alleviating steatosis, oxidative stress, and inflammation in chronic alcohol-fed mice.
Cao et al. (Mon,) studied this question.