Sun Mengjia, Zhong Pinfei, Xu Guishan, Zeng Wei, Yu Min, Cao Jiamin, Jin Jing, Chen Jie, Zhao Zhongxiang
State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, China.
Phytother Res. 2025 Jul;39(7):3046-3061. doi: 10.1002/ptr.8518. Epub 2025 May 8.
3-Oxo-22α-hydroxy-rotundic acid (ITP3) demonstrated notable hypolipidemic activity. However, the molecular mechanism of its hypolipidemic activity has not been elucidated. The present study aimed to evaluate its lipid-lowering efficacy using in vivo and in vitro hyperlipidemia models and to further elucidate its potential mechanism of action in hyperlipidemia. Endophytic fungi in plants of the genus Ilex were utilized for microbial transformation of rotundic acid (RA) to generate an adequate quantity of ITP3. Free fatty acid (FFA) treatment of HepG2 cells and C57BL/6J mice was used to evaluate the hypolipidemic effects of ITP3 in vivo and in vitro. A metabolomics approach combined with Western blot analysis was used to reveal the potential mechanism of the anti-hyperlipidemia of ITP3. The results showed that ITP3 exhibited good lipid-lowering activity in vivo and in vitro models of hyperlipidemia. In addition, metabolomics analysis revealed significant changes in serum and intracellular metabolite lipid levels, which were restored by ITP3. Mechanistically, ITP3 can inhibit lipid synthesis and activate lipid oxidation via the AMPK-SREBP-1c-PPARα pathway, thereby ameliorating lipid metabolism disorders. ITP3 exhibits a promising lipid-lowering effect via the AMPK-SREBP-1c-PPARα pathway, thereby improving lipid metabolism. This work highlights ITP3 as a potential phytochemical candidate for the treatment of hyperlipidemia.
3-氧代-22α-羟基-圆叶鼠李酸（ITP3）表现出显著的降血脂活性。然而，其降血脂活性的分子机制尚未阐明。本研究旨在利用体内和体外高脂血症模型评估其降脂效果，并进一步阐明其在高脂血症中的潜在作用机制。利用冬青属植物中的内生真菌对圆叶鼠李酸（RA）进行微生物转化，以产生足够量的ITP3。用游离脂肪酸（FFA）处理HepG2细胞和C57BL/6J小鼠，以评估ITP3在体内和体外的降血脂作用。采用代谢组学方法结合蛋白质免疫印迹分析来揭示ITP3抗高脂血症的潜在机制。结果表明，ITP3在体内和体外高脂血症模型中均表现出良好的降脂活性。此外，代谢组学分析显示血清和细胞内代谢物脂质水平发生了显著变化，而ITP3可使其恢复。机制上，ITP3可通过AMPK-SREBP-1c-PPARα途径抑制脂质合成并激活脂质氧化，从而改善脂质代谢紊乱。ITP3通过AMPK-SREBP-1c-PPARα途径表现出有前景的降脂作用，从而改善脂质代谢。这项工作突出了ITP3作为治疗高脂血症的潜在植物化学候选物的地位。
