Betulinic Acid Suppresses de novo Lipogenesis by Inhibiting Insulin and IGF1 Signaling as Upstream Effectors of the Nutrient-Sensing mTOR Pathway.

Despite its beneficial properties, effects of betulinic acid on the nutrient-sensing mTOR pathway via insulin or IGF1 signaling remain unclear. Here, we investigated whether betulinic acid reduces intracellular lipid accumulation via the nutrient-sensing pathway in HepG2 cells. Results showed that betulinic acid reduced intracellular lipid accumulation in a dose-dependent manner and inhibited the expression of de novo lipogenesis-related genes and proteins. RNA sequencing analysis revealed the transcriptional modulation of plasma membrane proteins by betulinic acid, and an in silico binding assay indicated an interaction between betulinic acid and IR or IGF1R. Furthermore, betulinic acid downregulated the post-translational modification of the canonical IRS1/PI3K/AKT-pT308 and IGF1/mTORC2/AKT-pS473 pathways, thereby reducing the activity of the mTOR/S6K/S6 pathway. These findings imply that betulinic acid suppresses hepatic lipid synthesis by inhibiting insulin and IGF1 signaling as upstream effectors of the nutrient-sensing mTOR pathway and could be a potent nutraceutical agent for the treatment of metabolic syndromes.