HO-1在酒精性脂肪肝中的致病作用及酒精诱导HO-1表达机制

Heme oxygenase-1 (HO-1) catalyzes heme catabolism toward biliverdin, carbon monoxide (CO), and free iron . HO-1 is cytoprotective and exerts anti-inflammatory effects. Serendipitously the applicant found aged transgenic mice were suffering from fatty liver. Alcohol is inducer for HO-1, however the exact role of HO-1 in alcohol induced fatty liver is unknown. Hence, the aim of this study was to establish mice model of alcohol induced fatty liver that mimic alcoholic liver disease history of alcohol abuser. Our study may offers an opportunity for investigation on HO-1 pathogenesis which based on creation of alcohol /miR-505、miR-760/HO-1 pathway and HO-1/iron/IRP/FASN 5′UTR –IRE”Triglycerides circuit in vivo and in vitro. We are offering a thorough understanding of HO-1 on not only protection, but also, to study pathogenesis which may reveal theoretical explanation and supplementary guide for treatment of alcohol induced fatty liver.

血红素氧化酶-1（heme oxygenase-1，HO-1）催化血红素分解产生铁、一氧化碳和胆绿素，对机体的保护作用。但申请者在其他研究中发现老龄HO-1转基因鼠患脂肪肝。酒精是HO-1诱导剂， HO-1在酒精性脂肪肝发病中究竟起何作用，是否为致病原因？为探讨HO-1的致病性，此项目将采用模拟酒精性肝病患者酗酒史建立酒精性脂肪肝小鼠模型，阐明“酒精/miR-505、miR-760/HO-1”的HO-1诱导表达机制；证明脂肪酸合酶（FASN）5′UTR 含有非典型的铁应答元件（IRE），其表达受铁浓度调控；以及”HO-1/铁/铁调节蛋白/FASN 5′UTR –IRE”的甘油三酯蓄积机制。HO-1参与酒精性脂肪肝的发生尚未见报道，本项研究将为酒精性脂肪肝的发病机制及治疗提供理论解释与补充，并将提示在利用HO-1保护作用的同时要注意其致病性。

血红素氧化酶-1(heme oxygenase-1，HO-1)催化血红素分解产生铁、一氧化碳和胆绿素，对机体具有保护作用。但申请者在其他研究中发现老龄HO-1转基因鼠出现患有脂肪肝的情况。酒精是HO-1诱导剂，HO-1在酒精性脂肪肝发病中究竟起何作用，是否为关键的致病因子? 为探讨HO-1的致病性，此项目采用模拟酒精性肝病患者酗酒史建立酒精性脂肪肝小鼠模型，拟阐明“酒精/miRNAs/HO-1”的HO-1诱导表达机制，证明胆固醇7α羟化酶-1（CYP7a1）mRNA 非编码区含有非典型的铁应答元件(IRE)，以及“HO-1/铁/铁调节蛋白/CYP7a1”的胆固醇蓄积作用机制。研究结果发现酒精能够下调miRNA-525-5p及miRNA-873，从而诱导HO-1的表达。HO-1过表达则会导致肝脏铁的沉积，沉积的铁进而通过铁调节蛋白作用于CYP7a1上的IRE结构，导致CYP7a1表达的下调，最终导致胆固醇蓄积并引起脂肪肝的发生。HO-1参与酒精性脂肪肝的发生尚未见报道，本项研究将为酒精性脂肪肝的发病机制及治疗提供理论解释与补充，并将提示在利用HO-1保护作用的同时要注意其致病性。