Xu Hongling, Yuan Mingming, Niu Kailin, Yang Wei, Jiang Maoyuan, Zhang Lei, Zhou Jing
School of Traditional Chinese Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Laboratory Animal Center Affiliate from Research Office, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China.
Molecules. 2024 Feb 23;29(5):976. doi: 10.3390/molecules29050976.
Metabolism-associated fatty liver disease (MAFLD), a growing health problem worldwide, is one of the major risks for the development of cirrhosis and liver cancer. Oral administration of nobiletin (NOB), a natural citrus flavonoid, modulates the gut microbes and their metabolites in mice. In the present study, we established a mouse model of MAFLD by subjecting mice to a high-fat diet (HFD) for 12 weeks. Throughout this timeframe, NOB was administered to investigate its potential benefits on gut microbial balance and bile acid (BA) metabolism using various techniques, including 16S rRNA sequencing, targeted metabolomics of BA, and biological assays. NOB effectively slowed the progression of MAFLD by reducing serum lipid levels, blood glucose levels, LPS levels, and hepatic IL-1β and TNF-α levels. Furthermore, NOB reinstated diversity within the gut microbial community, increasing the population of bacteria that produce bile salt hydrolase (BSH) to enhance BA excretion. By exploring further, we found NOB downregulated hepatic expression of the farnesoid X receptor () and its associated small heterodimer partner (), and it increased the expression of downstream enzymes, including cholesterol 7α-hydroxylase () and cytochrome P450 27A1 (). This acceleration in cholesterol conversion within the liver contributes to mitigating MAFLD. The present findings underscore the significant role of NOB in regulating gut microbial balance and BA metabolism, revealing that long-term intake of NOB plays beneficial roles in the prevention or intervention of MAFLD.
代谢相关脂肪性肝病（MAFLD）是一个在全球范围内日益严重的健康问题，是肝硬化和肝癌发生的主要风险之一。口服川陈皮素（NOB），一种天然柑橘类黄酮，可调节小鼠肠道微生物及其代谢产物。在本研究中，我们通过给小鼠喂食高脂饮食（HFD）12周建立了MAFLD小鼠模型。在此期间，给予NOB，使用包括16S rRNA测序、胆汁酸（BA）靶向代谢组学和生物学检测等各种技术，研究其对肠道微生物平衡和BA代谢的潜在益处。NOB通过降低血清脂质水平、血糖水平、LPS水平以及肝脏IL-1β和TNF-α水平，有效减缓了MAFLD的进展。此外，NOB恢复了肠道微生物群落的多样性，增加了产生胆汁盐水解酶（BSH）的细菌数量，以增强BA排泄。进一步探究发现，NOB下调了法尼醇X受体（FXR）及其相关小异二聚体伴侣（SHP）在肝脏中的表达，并增加了下游酶的表达，包括胆固醇7α-羟化酶（CYP7A1）和细胞色素P450 27A1（CYP27A1）。肝脏中胆固醇转化的加速有助于减轻MAFLD。本研究结果强调了NOB在调节肠道微生物平衡和BA代谢中的重要作用，表明长期摄入NOB在预防或干预MAFLD中发挥有益作用。
