The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

中文翻译：

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小檗碱通过调节多条通路预防非酒精性脂肪性肝炎的疾病进展

非酒精性脂肪性肝病 (NAFLD) 从单纯性脂肪变性 (NAFL) 到非酒精性脂肪性肝炎 (NASH) 的疾病进展受多种因素驱动。小檗碱 (BBR) 是一种古老的中药，对包括 NAFLD/NASH 在内的代谢性疾病具有多种有益作用。然而，由于所用 NASH 动物模型的局限性，其潜在机制仍未完全了解。方法：使用了高脂肪和高果糖饮食诱导的 NAFLD 小鼠模型，这是最好的临床前 NASH 小鼠模型。RNAseq、组织学和代谢途径分析用于鉴定 BBR 调节的潜在信号通路。LC-MS 用于测量血清和肝脏中的胆汁酸水平。实时 RT-PCR 和蛋白质印迹分析用于验证 RNAseq 数据。结果：BBR 不仅通过调节脂肪酸合成和代谢显着减少肝脏脂质积累，而且还通过靶向多种途径恢复胆汁酸稳态。此外，BBR 通过减少免疫细胞浸润和抑制中性粒细胞活化和炎症基因表达显着抑制炎症。此外，BBR 能够通过调节参与肝星状细胞活化和胆管细胞增殖的多个基因的表达来抑制肝纤维化。与我们之前的研究结果一致，BBR 的有益作用与 microRNA34a 和长链非编码 RNA H19 的下调有关，它们是促进 NASH 进展和肝纤维化的两个重要因素。结论：BBR 通过靶向多种途径成为 NASH 的一种有前途的治疗剂。这些结果为未来的临床研究奠定了坚实的基础。