Luo Zhixin, Li Mengqian, Yang Jiachuan, Li Jia, Zhang Yao, Liu Fang, El-Omar Emad, Han Lin, Bian Ji, Gong Lan, Wang Min
College of Food Science and Engineering, Northwest A&F University, Yangling, China.
Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia.
Front Nutr. 2022 Sep 21;9:976638. doi: 10.3389/fnut.2022.976638. eCollection 2022.
Ferulic acid (FA), a natural phenolic phytochemical abundantly present in whole grains, displays promising therapeutic effects on hypercholesterolemia while its underlying mechanism not fully elucidated. This study aimed to investigate the cholesterol-lowering effect of FA in high-fat diet (HFD)-fed mice and its potential molecular mechanism. FA supplementation alleviated HFD-induced hypercholesterolemia (-13.2%, < 0.05), along with increased excretion of bile acids (BAs) in feces (37.0%, < 0.05). Mechanism studies showed that FA activated the expression of cholesterol 7α hydroxylase (CYP7A1), a rate-limiting enzyme in BA biosynthesis in the liver, which increased the BAs biosynthesis from cholesterol. Surprisingly, increased excretion of BAs in feces is a consequence, not a cause, of CYP7A1 activation. Furthermore, enterohepatic farnesoid X receptor (FXR) signaling is not involved in the activation of hepatic CYP7A1 by FA. In conclusion, FA activates CYP7A1 through non-FXR signaling, which on the one hand effectively prevents hypercholesterolemia, and on the other hand leads to secondary BAs elevation in plasma. The latter may be the key to the anti-obesity and hypoglycemic effects of FA.
阿魏酸（FA）是一种大量存在于全谷物中的天然酚类植物化学物质，对高胆固醇血症显示出有前景的治疗效果，但其潜在机制尚未完全阐明。本研究旨在探讨FA对高脂饮食（HFD）喂养小鼠的降胆固醇作用及其潜在分子机制。补充FA可减轻HFD诱导的高胆固醇血症（-13.2%，P<0.05），同时粪便中胆汁酸（BAs）排泄增加（37.0%，P<0.05）。机制研究表明，FA激活了肝脏中BA生物合成的限速酶胆固醇7α羟化酶（CYP7A1）的表达，从而增加了从胆固醇合成BAs的量。令人惊讶的是，粪便中BAs排泄增加是CYP7A1激活的结果，而非原因。此外，肝肠法尼醇X受体（FXR）信号通路不参与FA对肝脏CYP7A1的激活。总之，FA通过非FXR信号通路激活CYP7A1，这一方面有效预防高胆固醇血症，另一方面导致血浆中继发性BAs升高。后者可能是FA抗肥胖和降血糖作用的关键。
