Ursolic acid alleviates lipid accumulation by activating the AMPK signaling pathway in vivo and in vitro

The mechanism underlying the effect of ursolic acid (UA) on lipid metabolism remains unclear. This study aimed to explore the mechanisms of UA in reducing lipid accumulation in free fatty acids-cultured HepG2 cells and in high-fat-diet-fed C57BL/6J mice. In vivo, UA effectively alleviated liver steatosis and decreased the size of adipocytes in the epididymis. It also significantly decreased the total cholesterol (TC) and triglyceride (TG) contents in the liver and plasma in C57BL/6 mice. In vitro, UA (20 µM) significantly reduced lipid accumulation; the intracellular TC contents decreased from 0.078 ± 0.0047 to 0.049 ± 0.0064 µmol/mg protein, and TG contents from 0.133 ± 0.005 to 0.066 ± 0.0047 µmol/mg protein, in HepG2 cells. Furthermore, UA reduced the mRNA expression related to fat synthesis, enhanced the mRNA expression related to adipose decomposition, and dramatically upregulated the protein expression of P-AMPK in vivo and in vitro. Of note, these protective effects of UA on a high-fat environment were blocked by the AMPK inhibitor (compound C) in vitro. In addition, the molecular docking results suggested that UA could be docked to the AMPK protein as an AMPK activator. These results indicated that UA lowered the lipid content probably via activating the AMPK signaling pathway, thereby inhibiting lipid synthesis and promoting fat decomposition. PRACTICAL APPLICATION: Ursolic acid (UA) widely exists in vegetables and fruits. This study highlighted a lipid-lowing mechanism of UA in HepG2 cells and C57BL/6J mice. The data indicated that UA might be used in lipid-lowering functional foods.