NMN restores hepatic Hamp, alleviating alcohol-associated liver disease in mice via C/EBPα signaling

Chronic alcohol consumption leads to alcohol-associated liver disease (ALD), a severe condition characterized by hepatic steatosis, inflammation, and liver injury. A critical pathological hallmark and pathogenic basis for ALD is the reduction of hepatic nicotinamide adenine dinucleotide (NAD+) levels, which impairs cellular energy metabolism and redox balance. Current treatments for ALD are often limited in efficacy, highlighting an urgent need for novel therapeutic strategies. Nicotinamide mononucleotide (NMN), a natural NAD+ precursor found in various dietary sources, has garnered attention for its potential to restore NAD+ levels and mitigate metabolic dysfunction, making it a promising candidate for ALD intervention.

Researchers investigated the therapeutic effects of nicotinamide mononucleotide (NMN) supplementation in a mouse model of chronic alcohol-fed ALD. The study assessed NMN's impact on hepatic lipid deposition, lipid metabolism genes, oxidative stress, and inflammation, ultimately evaluating its ability to ameliorate liver injury. Mechanistic insights were gained through transcriptomics-based analysis to identify key pathways. Further in vitro experiments involved Hamp knockdown in ethanol-treated hepatocytes to confirm the role of hepcidin antimicrobial peptide (Hamp) in NMN's protective effects. The study also explored the transcriptional regulation of Hamp by NMN.

NMN supplementation effectively attenuated the NAD+ decline observed in ALD mice. This restoration of NAD+ levels was associated with a significant attenuation of hepatic lipid deposition, normalization of dysregulated lipid metabolism genes, and a reduction in both oxidative stress and inflammation, ultimately leading to ameliorated liver injury. A key mechanistic finding from transcriptomics analysis revealed that alcohol-reduced hepcidin antimicrobial peptide (Hamp) expression was rescued by NMN, alongside the recovery of circulatory and hepatic iron levels. The study found that hepatic Hamp expression is positively associated with NAD+ content in the liver.

Hamp knockdown in ethanol-treated hepatocytes significantly abolished NMN-improved lipid accumulation and the dysregulation of lipid metabolism-related genes, underscoring Hamp's critical role in NMN's protective mechanism. Further analysis identified a C/EBPα-involved transcriptional regulation mechanism underlying NMN's protective effect on Hamp in ALD, establishing a novel C/EBPα/Hamp signaling axis.