Gypenosides Ameliorate Hyperlipidemia by Activating Lipophagy through Modulation of the AMPK/mTOR/ULK1 Signaling Pathway

Due to the complex regulatory mechanisms of cholesterol absorption, synthesis, and metabolism in patients with hyperlipidemia, doubling the dosage of statins reduced the serum low-density lipoprotein cholesterol (LDL-C) level by only 6%. The clinical research found that gypenosides (Gyps), as a natural PCSK9 inhibitor, can further reduce lipid levels in hyperlipidemia patients on top of atorvastatin, breaking through the "6% rule of statins". Results demonstrated that Gyps significantly reduced hepatic lipid content, decreased lipid droplet (LDs) accumulation in liver tissue, alleviated the degree of hepatic steatosis, and activated the autophagy in high-fat diet (HFD)-fed golden Syrian hamsters. Gyps reduced lipid deposition in free fatty acid (FFA)-stimulated HepG2 cells and promoted clearance of LDL-C from the blood by activating lipophagy through the regulation of the AMPK/mTOR/ULK1 signaling pathway. This lipophagy activation led to the intracellular metabolism of lipids, achieving the goal of lipid reduction. Gyps-induced lipophagy effectively decreased lipid levels without hepatotoxicity.