Peng Shang, Meng Moran, Luo Ping, Liu Jiao, Wang Junjun, Chen Yong
Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, College of Health Science and Engineering, Hubei University, Wuhan 430062, China.
Int J Mol Sci. 2025 Jan 22;26(3):895. doi: 10.3390/ijms26030895.
The aim of this study was to investigate the protective effects and potential mechanisms of Tetrahydrocurcumin (THC) on methionine-choline-deficient diet (MCD)-induced MASH in C57BL/6 mice by using multi-omics techniques. The C57BL/6 mice were fed with the MCD for 8 weeks to establish a MASH model, while THC (100 mg·kg·d) and obeticholic acid (6.5 mg·kg·d) were administered via gavage to the THC group and the positive control group, respectively. The biochemical indexes of the serum and liver were detected using kits. Liver tissue sections were taken to observe the pathomorphological changes. Serum lipid and bile acid contents were measured via LC-MS, and the changes in ileal intestinal flora were detected by 16S rDNA high-throughput sequencing technology. The results revealed that THC significantly attenuated oxidative stress and lipid accumulation in NCTC-1469 cells and relieved hepatic injury and oxidative stress, reduced hepatic TG content, and improved hepatic steatosis in mice. THC alleviated 34 lipid abnormalities caused by the MCD; increased the abundance and diversity of intestinal flora, the ratio of to , and the abundance of the probiotic (, , , , ); and reduced the abundance of obesity-associated pathogenic flora such as . Bile acid analysis showed that THC administration reduced the levels of serum toxic bile acid 7-KDCA and CA. In addition, RT-qPCR studies showed that THC down-regulated the transcript levels of the hepatic lipogenesis-related genes , , , and , and up-regulated the transcript levels of the hepatic bile acid secretion-related genes and . The above results suggest that THC may alleviate MCD-induced MASH by downregulating liver , , , and levels to inhibit lipid synthesis, upregulating and levels to regulate serum toxic BA levels, up-regulating the abundance of intestinal probiotic flora, and down-regulating the abundance of intestinal harmful bacterial flora. The multi-omics findings from the above study identified potential new mechanisms by which THC alleviates MASH, providing new reference targets for the development of anti-MASH drugs. These results also offer a basis for screening clinical diagnostic biomarkers for MASH and provide new directions for personalized diagnosis and treatment.
本研究旨在运用多组学技术，探究四氢姜黄素（THC）对蛋氨酸-胆碱缺乏饮食（MCD）诱导的C57BL/6小鼠非酒精性脂肪性肝炎（NASH）的保护作用及潜在机制。将C57BL/6小鼠喂食MCD 8周以建立NASH模型，而分别对THC组和阳性对照组经口灌胃给予THC（100 mg·kg·d）和奥贝胆酸（6.5 mg·kg·d）。使用试剂盒检测血清和肝脏的生化指标。取肝脏组织切片观察病理形态学变化。通过液相色谱-质谱联用（LC-MS）测定血清脂质和胆汁酸含量，并采用16S rDNA高通量测序技术检测回肠肠道菌群的变化。结果显示，THC显著减轻了NCTC-1469细胞中的氧化应激和脂质积累，缓解了小鼠的肝损伤和氧化应激，降低了肝脏甘油三酯（TG）含量，并改善了肝脏脂肪变性。THC减轻了由MCD引起的34种脂质异常；增加了肠道菌群的丰度和多样性、拟杆菌属与厚壁菌门的比例以及益生菌（双歧杆菌属、乳杆菌属、阿克曼菌属、普氏菌属、嗜黏蛋白阿克曼菌）的丰度；并降低了如脱硫弧菌属等与肥胖相关的致病菌群的丰度。胆汁酸分析表明，给予THC可降低血清毒性胆汁酸7-酮脱氧胆酸（7-KDCA）和胆酸（CA）的水平。此外，逆转录-定量聚合酶链反应（RT-qPCR）研究表明，THC下调了肝脏脂肪生成相关基因脂肪酸合酶（FAS）、乙酰辅酶A羧化酶α（ACCα）、固醇调节元件结合蛋白-1c（SREBP-1c）和脂肪酸转运蛋白2（FATP2）的转录水平，并上调了肝脏胆汁酸分泌相关基因胆盐输出泵（BSEP）和多药耐药相关蛋白2（MRP2）的转录水平。上述结果表明，THC可能通过下调肝脏FAS、ACCα、SREBP-1c和FATP2水平以抑制脂质合成，上调BSEP和MRP2水平以调节血清毒性胆汁酸水平，上调肠道益生菌群的丰度以及下调肠道有害菌菌群的丰度来减轻MCD诱导的NASH。上述研究的多组学结果确定了THC减轻NASH的潜在新机制，为抗NASH药物的开发提供了新的参考靶点。这些结果也为筛选NASH的临床诊断生物标志物提供了依据，并为个性化诊断和治疗提供了新方向。
