An ATF3 Inducer Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease Through the AMPK and PKA Pathways

Obesity is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular mechanisms and effective treatments remain unclear. This study investigated whether ST32db, an inducer of activating transcription factor 3 (ATF3), affects lipid metabolism in MASLD. An in vitro model was established involving the treatment of HepG2 cells with 1 mM oleic acid (OA) with or without 20 µM ST32db. In an in vivo model, C57BL/6 mice were fed a high-fat diet (HFD) for 18 weeks to induce obesity and treated or not with ST32db (1 mg kg^-1). ST32db significantly decreased intracellular lipid accumulation in OA-treated HepG2 cells. In these cells, ST32db remarkably decreased mRNA and protein levels of adipogenesis- and lipogenesis-related genes and increased mRNA levels of adipose triglyceride lipase (ATGL), a lipolytic enzyme. In HFD-fed mice, the ST32db treatment significantly decreased the liver weight, serum triglycerides, and fat vacuole and triglyceride accumulation in the liver. Livers from these mice also showed significantly decreased CCAAT/enhancer-binding protein β mRNA and protein levels, increased ATF3 mRNA and protein and ATGL mRNA levels, and increased levels of phosphorylated AMP-activated protein kinase (AMPK) and protein kinase A (PKA). These findings suggest that ST32db may exert protective effects against MASLD through activating hepatic AMPK and PKA pathways.