Hepatic NMNAT1 is required to defend against alcohol-associated fatty liver disease

Sci Adv. 2025 Jun 27;11(26):eadt6195. doi: 10.1126/sciadv.adt6195. Epub 2025 Jun 27.

Abstract

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), a nicotinamide adenine dinucleotide (NAD+) synthetase in Preiss-Handler and salvage pathways, governs nuclear NAD+ homeostasis. This study investigated the role of NMNAT1 in alcohol-associated liver disease (ALD). Decreased NMNAT1 expression and activity were observed in the liver of patients with alcohol-associated hepatitis and either liver or primary hepatocytes from ALD mice. F-box and WD repeat domain containing 7 (FBXW7)-regulated interferon regulatory factor 1 (IRF1) ubiquitination degradation contributed to the alcohol-inhibited NMNAT1 transcriptional level. Hepatic NMNAT1 knockout aggravated alcohol-induced hepatic NAD+ decline and further hepatic steatosis and liver injury. Metabolomics and transcriptomics interaction revealed that the cysteine sulfinic acid decarboxylase (CSAD)-regulated taurine pathway was involved in NMNAT1-disrupted hepatic lipid metabolism in ALD. Hepatic CSAD overexpression or taurine supply attenuated hepatic NMNAT1 knockout-aggravated ALD. Hepatic NMNAT1 loss inhibited NMN-protected ALD. Replenishing hepatic NMNAT1 reversed liver lipid accumulation in ALD mice. These findings identified NMNAT1 as a promising therapeutic target for ALD.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Fatty Liver, Alcoholic* / genetics
  • Fatty Liver, Alcoholic* / metabolism
  • Fatty Liver, Alcoholic* / pathology
  • Hepatocytes / metabolism
  • Humans
  • Interferon Regulatory Factor-1 / metabolism
  • Lipid Metabolism
  • Liver* / metabolism
  • Liver* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nicotinamide-Nucleotide Adenylyltransferase* / genetics
  • Nicotinamide-Nucleotide Adenylyltransferase* / metabolism

Substances

  • Nicotinamide-Nucleotide Adenylyltransferase
  • Interferon Regulatory Factor-1