SMPD3 Inhibition Contributes to Nicotinamide-Ameliorated Hepatic Steatosis in Chronic Alcohol-Fed Mice.

Alcohol-associated liver disease (ALD) is characterized by the reduction of hepatic nicotinamide adenine dinucleotide (NAD), which exacerbates hepatic steatosis. The present study was conducted to investigate the protective role of nicotinamide (NAM), a foodborne precursor of NAD biosynthesis, in ALD. C57BL/6N mice were employed to establish the ALD model and were administered NAM by gavage. Our results showed that NAM supplementation significantly ameliorated alcohol-induced NAD reduction and lipid accumulation in both mice liver and cultured AML-12 hepatocytes and improved lipid metabolism-associated gene disorders. Alcohol-induced liver injury and oxidative stress were also blocked by NAM administration. Further transcriptomics analysis and validation revealed that alcohol-stimulated sphingomyelin phosphodiesterase 3 (SMPD3) was significantly reversed by NAM, along with the reduction of hepatic ceramide levels. Importantly, SMPD3 was upregulated in the livers of ALD patients. Genetically silencing SMPD3 alleviated alcohol-induced lipid accumulation in hepatocytes. ChIP assay identified SMPD3 as a direct downstream target of hypoxia-inducible factor 1 alpha (HIF-1α). Liver-specific knockdown reduced the level of hepatic SMPD3 expression in mice. Activation of HIF-1α abolished the prevention of intrahepatic liver lipid deposition by NAM, while SMPD3 knockdown reversed HIF-1α activation-stimulated lipid accumulation, indicating that a HIF-1α-regulated SMPD3 pathway was involved in the beneficial role of NAM. NAM improved liver oxidative stress, while antioxidant MitoQ administration rescued HIF-1α/SMPD3 activation in ALD mice, implying that the antioxidant effect of NAM contributed to its inhibitory role on the HIF-1α/SMPD3 pathway. In conclusion, NAM ameliorates chronic alcohol intake-induced hepatic steatosis by inhibiting SMPD3. This study provides new insights into the mechanistic understanding of ALD and highlights NAM as a therapeutic choice for ALD treatment.