Esculeogenin A

Esculeogenin A is the aglycone of the tomato saponin, Esculeoside A. It is an orally active compound with hepatoprotective, lipid-lowering, and antioxidant properties. Esculeogenin A regulates molecular targets such as PPARα, SREBP1, Nrf2, NF-κB, and ACAT1/ACAT2, promoting hepatic fatty acid oxidation, inhibiting de novo lipogenesis, enhancing antioxidant defense, and suppressing inflammatory responses. It improves liver function, alleviates hyperlipidemia, and inhibits hepatic steatosis and foam cell formation. Additionally, it prevents non-alcoholic fatty liver disease in high-fat diet-fed rats and reduces atherosclerotic lesions in apoE-deficient mice. Esculeogenin A is useful for research related to non-alcoholic fatty liver disease, atherosclerosis, and hyperlipidemia.

Esculeogenin A in varying concentrations over 24 hours can dose-dependently inhibit the accumulation of cholesterol esters in acetylated low-density lipoprotein-induced human monocyte-derived macrophages without affecting triglyceride accumulation and does not induce cytotoxicity. At a 5-hour exposure, it does not inhibit the binding or degradation of acetylated low-density lipoproteins in these macrophages. Additionally, Esculeogenin A over 24 hours inhibits cholesterol ester accumulation in Chinese hamster ovary (CHO) cells overexpressing human ACAT-1 or human ACAT-2 in a dose-dependent manner, without causing cytotoxicity. When applied for 15 minutes, it inhibits ACAT activity within human monocyte-derived macrophages, CHO cells expressing human ACAT-1, and CHO cells expressing human ACAT-2, dose-dependently reducing ACAT activity in HMDMs by 40% at 50 μmol/L. Esculeogenin A also reduces ACAT-1 protein expression in monocyte-derived macrophages dose-dependently over 24 hours while not affecting the expression of SR-A or SR-BI. At concentrations between 10-100 μM over 24 hours, it effectively inhibits cholesterol ester accumulation appreciably in HMDMs, without altering the uptake or degradation of acetylated LDL, achieving a 40% reduction at a 50 μM concentration. It also suppresses cholesterol ester accumulation dose-dependently in both hACAT-1 CHO and hACAT-2 CHO cells and inhibits ACAT activity across human monocyte-derived macrophages, hACAT-1 CHO cells, and hACAT-2 CHO cells. Finally, in the range of 10-50 μM over 24 hours, Esculeogenin A decreases ACAT-1 protein expression in HMDMs dose-dependently while not affecting the expression of SR-A or SR-BI.

Esculeogenin A, administered orally at 50-200 mg/kg once daily for 12 weeks, ameliorates non-alcoholic fatty liver disease in high-fat diet (HFD) fed rats in a dose-dependent manner. It achieves this by normalizing liver enzymes and lipid levels, improving liver histological features, activating the Nrf2 antioxidant pathway, inhibiting NF-κB-mediated inflammatory responses, and regulating hepatic lipogenesis and fatty acid oxidation. Notably, a dose of 200 mg/kg restores most parameters to near control levels. Additionally, Esculeogenin A (100 mg/kg/day; orally; administered daily for 90 consecutive days) is a metabolite of orally administered Esculeoside A and can be detected in the aorta of apolipoprotein E-deficient mice.