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

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