NAMPT improves high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) via the SIRT1–C/EBPβ–STEAP4–NRF2 axis

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic condition, yet therapeutic targets remain elusive. Nicotinamide phosphoribosyl transferase (NAMPT) and six-transmembrane epithelial antigen of the prostate 4 (STEAP4) are integral regulators in various metabolic disorders. This study investigates the role and molecular mechanisms of NAMPT in NAFLD pathogenesis. We found that inhibiting NAMPT or knockdown of silent information regulator 1 (SIRT1) exacerbates liver steatosis and impairs hepatic antioxidant defenses in high-fat diet (HFD)-induced obese mice, while reducing STEAP4 expression, suggesting that NAMPT and SIRT1 are pivotal in NAFLD progression and may regulate STEAP4. The role of NAMPT in SIRT1 expression involves nicotinamide adenine dinucleotide (NAD) synthesis. Our results indicate that inhibiting SIRT1's deacetylase activity impairs CCAAT/enhancer-binding protein β (C/EBPβ) deacetylation and consequently its function. Additionally, STEAP4, previously identified as a C/EBPβ target, can upregulate the expression and nuclear translocation of NF-E2-related factor 2 (NRF2) to combat oxidative stress in NAFLD. This study confirms that NAMPT ameliorates NAFLD via the SIRT1-C/EBPβ-STEAP4-NRF2 signaling axis in HFD-induced obese mice, proposing a novel strategy for the prevention and treatment of NAFLD.