小檗碱预防肝脏脂肪沉积向脂肪性肝炎和纤维化发展的作用和机制研究

The spectrum of nonalcoholic fatty liver disorders ranges from hepatic steatosis to steatohepatitis and cirrhosis. nonalcoholic steatohepatitis (NASH) can have serious consequences，as it is more likely to progress to fibrosis and cirrhosis. Endoplasmic reticulum (ER) stress is in the central role of the regulation of NAFLD. Inhibition of ER stress can ameliorate triglycerides accumulation and ER may be a target for pharmacologic interventions. We did lots of foundational work in dissecting the mechanism of berberine in NAFLD treatment. Our results showed that ER stress signaling and hepatic lipogenesis were co-regulated by berberine which reduced hepatic lipid accumulation in both in vivo and in vitro NAFLD models. Lipoperoxides in liver was inhibited by berberine. The beneficial effect of berberine on NAFLD may be mediated via the suppression of ER stress signaling. Based on our previous work, our project will further evaluate the effect of berberine in NAFLD treatment in vivo by using the NAFLD mouse models, and we will explain the mechanism of berberine in vitro as well. We will reveal the molecular target and mechanism of beberine in treating NAFLD through inhibition of ER stress, and assess the feasibility of using berberine as a prospective choice for NAFLD treatment. As mentioned above, our data will be helpful for the clinical use of berberine and developing more new traditional Chinese medicine as a leading compound in NAFLD treatment, which will be of great significance in scientific research and clinical application.

非酒精性脂肪肝（NAFLD）包括单纯的肝脏脂肪沉积、非酒精性肝炎（NASH）和肝硬化。NASH 是由单纯性脂肪肝向肝纤维化、肝硬化转化的关键点。内质网应激在NAFLD发生发展中具有核心意义。前期工作显示小檗碱治疗后，显著改善模型动物的肝脏脂质沉积，内质网应激亦被显著抑制，肝脏中的过氧化水平减少，对炎症、凋亡和纤维化也显示了潜在的抑制作用。在细胞水平，经小檗碱干预可显著降低油酸/棕榈酸引起的肝原代细胞甘油三酯含量升高，并抑制衣霉素诱导的内质网应激。鉴于上述重要结果，本课题将在此基础上，从细胞，分子和动物整体水平，多角度全面评价小檗碱治疗NAFLD药理学作用，挖掘其负调控内质网应激进而改善肝脏脂质沉积并预防其向NASH恶化的分子机制。这对阐述小檗碱治疗NAFLD作用机制及NAFLD发病过程中内质网应激的作用至关重要，并对将来基于内质网为治疗靶点的中药先导化合物的开发具有重要参考价值和实际意义。

非酒精性脂肪肝（NAFLD）包括单纯的肝脏脂肪沉积、非酒精性肝炎（NASH）和肝硬化。NASH 是由单纯性脂肪肝向肝纤维化、肝硬化转化的关键点。内质网应激在NAFLD发生发展中具有核心意义。我们的工作显示小檗碱治疗后，显著改善模型动物的肝脏脂质沉积，内质网应激亦被显著抑制，肝脏中的过氧化水平减少，对炎症、凋亡和纤维化也显示了潜在的抑制作用。在细胞水平，经小檗碱干预可显著降低油酸/棕榈酸引起的肝原代细胞甘油三酯含量升高，并抑制衣霉素诱导的内质网应激。我们从细胞，分子和动物整体水平，多角度全面评价小檗碱治疗NAFLD药理学作用，挖掘其负调控内质网应激进而改善肝脏脂质沉积并预防其向NASH恶化的分子机制。这对阐述小檗碱治疗NAFLD作用机制及NAFLD发病过程中内质网应激的作用至关重要，并对将来基于内质网为治疗靶点的中药先导化合物的开发具有重要参考价值和实际意义。