Wang Li-Tian, Yin Huai-Liu, Jin Ya-Min, Hu Dan-Dan, Yang Xiang-Xuan, Sheng Jun, Huang Ye-Wei, Wang Xuan-Jun
Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China; Faculty of basic medical science, Kunming medical university, Kunming, China.
Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, China; College of Food Science and Technology, Yunnan Agricultural University, Kunming, China.
Nutrition. 2025 Jun;134:112717. doi: 10.1016/j.nut.2025.112717. Epub 2025 Feb 18.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) hinders the clearance of low-density lipoprotein cholesterol (LDL-C) by promoting the degradation of the low-density lipoprotein receptor (LDLR), leading to the accumulation of LDL-C and thus becoming an important cause of atherosclerosis. Ellagic acid, a naturally occurring polyphenol widely present in fruits, vegetables, and nuts, has attracted significant attention due to its potential role in the prevention and treatment of cardiovascular diseases. However, the molecular mechanisms by which ellagic acid alleviates atherosclerosis by inhibiting PCSK9 are not fully understood.
This study further validated the mechanism of action of ellagic acid through in vitro HepG2 cell experiments and a high-fat diet-induced ApoE mouse model.
The results showed that ellagic acid significantly reduced the expression and secretion of PCSK9 while upregulating LDLR protein levels; its mechanism is related to the inhibition of hepatocyte nuclear factor 1α (HNF1α) expression and the promotion of forkhead box O3 (FoxO3) expression increase. Additionally, ellagic acid reduced aortic plaque deposition in mice induced by a high-fat diet; consistent with the in vitro experimental results, ellagic acid lowered the expression and secretion of PCSK9 and elevated LDLR protein levels by inhibiting HNF1α and increased FoxO3 expression.
In summary, this study demonstrates that ellagic acid inhibits PCSK9 by regulating HNF1α and FoxO3, thereby increasing LDLR levels and alleviating atherosclerosis. This finding not only consolidates the scientific basis of plant-based diets for preventing cardiovascular diseases but also provides an important direction for developing functional foods and nutritional intervention strategies based on natural polyphenols.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）通过促进低密度脂蛋白受体（LDLR）的降解来阻碍低密度脂蛋白胆固醇（LDL-C）的清除，导致LDL-C积累，从而成为动脉粥样硬化的重要原因。鞣花酸是一种广泛存在于水果、蔬菜和坚果中的天然多酚，因其在心血管疾病预防和治疗中的潜在作用而备受关注。然而，鞣花酸通过抑制PCSK9减轻动脉粥样硬化的分子机制尚未完全明确。
本研究通过体外HepG2细胞实验和高脂饮食诱导的ApoE小鼠模型进一步验证了鞣花酸的作用机制。
结果表明，鞣花酸显著降低PCSK9的表达和分泌，同时上调LDLR蛋白水平；其机制与抑制肝细胞核因子1α（HNF1α）表达以及促进叉头框O3（FoxO3）表达增加有关。此外，鞣花酸减少了高脂饮食诱导的小鼠主动脉斑块沉积；与体外实验结果一致，鞣花酸通过抑制HNF1α降低PCSK9的表达和分泌，并通过增加FoxO3表达提高LDLR蛋白水平。
综上所述，本研究表明鞣花酸通过调节HNF1α和FoxO3抑制PCSK9，从而增加LDLR水平并减轻动脉粥样硬化。这一发现不仅巩固了植物性饮食预防心血管疾病的科学依据，也为开发基于天然多酚的功能性食品和营养干预策略提供了重要方向。
