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

Phloretin is a natural dihydrochalcone with a variety of biological activities. Its potential in modulating lipid metabolism in vitro and in vivo with HepG2 and C. elegans was investigated in this study. Phloretin significantly diminished lipid accumulation and ROS levels, mitigated the degree of lipid peroxidation, and ameliorated mitochondrial dysfunction in HepG2 cells. The expression levels of lipid synthesis genes (SREBP and FASN) were downregulated, while PI3K-AKT related genes (AKT, FOXO, MTOR) were upregulated. Furthermore, phloretin significantly alleviated the detrimental effects of lipid accumulation on growth indices and locomotor ability in C. elegans. It also reduced lipofuscin, ROS level as well as glucose and triglyceride contents, significantly affected amino acid and lipid metabolism pathways based on metabolomics profiles and analysis. Gene expression levels of sbp-1, mdt-15, fat-5, fat-6, and fat-7 were markedly down-regulated following treatment with phloretin, while daf-16, age-1 and skn-1were significantly up-regulated. Tests with mutant C. elegans strains of daf-16, age-1, sbp-1 and nhr-49 further confirmed that the phloretin-induced decrease in lipid accumulation was attributed to the inhibition of lipid biosynthesis pathway by IIS and sbp-1/SREBP. Our study indicated that phloretin exerted hypolipidemic effects in vitro and in vivo, providing a basic foundation for considering phloretin as a phytochemical candidate for regulating lipid metabolism and preventing hyperlipidemia.