ARRB1通过促进自噬缓解非酒精性脂肪肝的机制研究

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, but its pathogenesis and treatment are not fully understood. It is very important to intensive study on the mechanism of NAFLD. ARRB1 is a multifunctional signal transduction molecule and a potential target for metabolic diseases. With diverse regulation of autophagy, ARRB1 plays a different role in different tissues and organs, but its role in the regulation of autophagy in NAFLD has not been reported. In the preliminary study, we found that serum ARRB1 levels of NAFLD were significantly decreased, which were negatively correlated with lipid metabolism. To investigate the potential mechanism, we used recombinant lentivirus vectors and liver specific adeno-associated virus carrying ARRB1 gene or siRNA fragment of ARRB1 to bidirectional regulate the ARRB1 level in the cells and liver respectively. Then we observed the effect of ARRB1 on lipid metabolism. Furthermore, we examined the regulation of autophagy by ARRB1 in hepatocytes and tissues to study the possible role of ARRB1 in different stages of autophagy. In conclusion, we described the pattern and mechanism of ARRB1 mediated autophagy in the development and progression of NAFLD from three levels of clinical samples, cultured cells and animal model. These results may provide new experimental basis and potential therapeutic targets for NAFLD.

非酒精性脂肪肝（NAFLD）已成为最常见的肝脏疾病，但其发病机制尚未完全明确，缺乏有效治疗手段，深入研究NAFLD发病机理，具有十分重要的意义。ARRB1是具有多种功能的信号传导分子，是代谢相关性疾病的潜在靶点。ARRB1对细胞自噬的调节具有多样性，在不同的组织中发挥不同的作用，但其调控的自噬在NAFLD中作用未见报道。我们检测NAFLD患者血清样本发现，ARRB1含量显著降低，与脂代谢呈负相关。为研究其作用机制，我们采用慢病毒在细胞中双向调节ARRB1水平，利用肝脏特异性腺相关病毒感染小鼠，靶向调节肝脏ARRB1水平，观察其对脂代谢的影响。而后进一步检测ARRB1对自噬的调节，深入研究ARRB1对自噬发生不同阶段的调控机制。从临床样本、细胞和动物模型三个水平阐述ARRB1介导的自噬在NAFLD中调控脂代谢的作用方式和规律，为NAFLD的发病机制提供新的实验依据并为其治疗提供新的潜在靶点。

非酒精性脂肪肝（NAFLD）已成为最常见的肝脏疾病，但其发病机制尚未完全明确，缺乏有效治疗手段，深入研究NAFLD发病机理，具有十分重要的意义。β抑制蛋白1（ARRB1）是具有多种功能的信号传导分子，是代谢相关性疾病的潜在靶点。ARRB1对细胞自噬的调节具有多样性，在不同的组织中发挥不同的作用，但其调控的自噬在脂代谢中作用未见报道。我们将通过收集NAFLD患者血清标本，检测ARRB1的含量变化及与其他生物学指标的相关性。采用慢病毒载体在细胞模型中双向调节ARRB1的水平，随后检测甘油三酯和胆固醇代谢相关基因和蛋白的改变，观察ARRB1对脂代谢的影响。而后进一步检测ARRB1对肝细胞自噬的调节。从临床样本、细胞和动物三个水平阐述ARRB1介导的自噬调控肝脏脂代谢的作用方式和规律，为NAFLD的发病机制提供新的实验依据并为其治疗提供新的潜在靶点。研究结果显示，NAFLD患者血脂和转氨酶水平高于正常对照，而血清ARBB1水平显著降低。相关分析表明，ARRB1与BMI、甘油三酯、总胆固醇、低密度脂蛋白、ALT、AST及GGT水平成负相关。我们成功构建了ARRB1过表达及抑制的慢病毒载体，研究发现，ARRB1可能通过PPARγ-ATGL途径调控甘油三酯代谢，通过INSIG2-SREBP2-LDLr途径调控胆固醇代谢。ARRB1能够促进肝细胞自噬，因此ARRB1激活肝细胞自噬，恢复异常的自噬功能是治疗肝脏并发症的一个潜在有效途径。综上所述，ARRB1在调节脂代谢方面均有重要的作用，本研究为NAFLD的发病机制提供新的实验依据并为其治疗提供新的潜在靶点。