The natural dihydrochalcone phloretin reduces lipid accumulation via downregulation of IIS and sbp-1/SREBP pathways in HepG2 cells and Caenorhabditis elegans

Phloretin, a natural dihydrochalcone, exhibits significant potential in modulating lipid metabolism both in vitro and in vivo. This study investigated the effects of phloretin on lipid accumulation in HepG2 cells and Caenorhabditis elegans. In HepG2 cells, phloretin reduced lipid accumulation, ROS levels, and lipid peroxidation while ameliorating mitochondrial dysfunction. It downregulated lipid synthesis genes (SREBP, FASN) and upregulated PI3K-AKT pathway genes (AKT, FOXO, MTOR). In C. elegans, phloretin alleviated lipid accumulation-induced growth and locomotor impairments, reduced lipofuscin, ROS, glucose, and triglyceride levels, and modulated amino acid and lipid metabolism pathways. Gene expression analysis revealed downregulation of sbp-1, mdt-15, fat-5, fat-6, and fat-7, and upregulation of daf-16, age-1, and skn-1. Mutant studies confirmed that phloretin's lipid-lowering effects were mediated through the IIS and sbp-1/SREBP pathways. These findings suggest phloretin is a promising candidate for regulating lipid metabolism and preventing hyperlipidemia.