非酒精性脂肪肝（Non Alcoholic Fatty Liver Disease，NAFLD）在我国发病率逐年升高，可进展为肝炎、肝硬化。近年来研究发现脂肪沉积过程中存在铁调节异常及氧化应激。我们研究发现，血红素氧合酶/一氧化碳（heme oxygenase/carbon monoxide，HO/CO）通路在肝病过程中被激活并参与肝内铁代谢及抗氧化；“调肝理脾方”能改善NAFLD患者临床症状，但其机制不清。文献报道“调肝理脾方”中多味中药能诱导HO-1表达。因此，我们提出“调肝理脾方”可能干预HO/CO通路，调节肝内铁代谢和氧化应激改善NAFLD脂肪沉积，发挥保肝作用。本项目采用脂肪细胞和高脂饮食诱导NAFLD大鼠模型，探讨“调肝理脾方”治疗NAFLD的特点及分子机制，为“调肝理脾”法治疗NAFLD提供理论依据。

Nonalcoholic fatty liver disease (NAFLD) have increased incidence in China and it may progress to hepatitis and cirrhosis. Abnormal iron metabolism and oxidative stress were found in NAFLD. We found Heme oxygenase/carbon monoxide (HO/CO) was activated in liver diseases process and it participates in iron metabolism andantioxidant effect. Our study showed “Tiao gan Li pi” Decoction could alleviate NAFLD patient’s symptoms, but the mechanism is unclear. Some literatures reported several herbs of “Tiao gan Li pi” Decoction induced HO-1 expression. Therefore we hypothesize that “Tiao gan Li pi” Decoction have liver protective effect, may regulate iron metabolism and oxidative stress through HO/CO pathway. We will use fat cells and high-fat diet-induced NAFLD rat model, discuss “Tiao gan Li pi” Decoction treat NAFLD characteristic and molecular mechanism. We will provide an evidence for “Tiao gan Li pi” of traditional Chinese medicine treat NAFLD.

非酒精性脂肪肝目前发病率较高，目前认为胰岛素抵抗、炎症刺激等参与其中，临床缺乏有效的治疗药物。非酒精性脂肪肝病人发现有铁沉积的现象，前期实验提示肝病HO-1表达升高，HO-1与铁沉积的在脂肪肝病进展中的具体机制不清。我科“调肝理脾方”在临床治疗非酒精性脂肪肝取得了较好的疗效，本课题从高脂诱导的脂肪肝大鼠模型和脂肪细胞模型，从体内到体外，研究“调肝理脾方”治疗脂肪肝是否通过调节HO-1表达及铁代谢稳态的机制。研究显示，经过8周高脂饮食饲养的大鼠，非酒精性脂肪肝模型成功，分别给予钴原卟啉（Copp）、锌原卟啉诱导（Znpp）和抑制HO-1表达，给予高中低剂量“调肝理脾方”中药治疗4周，共12周，结果显示模型组大鼠肝内铁沉积为阳性，可见炎症细胞浸润，Copp能显著提高肝内HO-1表达，肝脏铁沉积加重，Znpp抑制HO-1表达减轻肝损伤，降低脂肪沉积，可能是通过调节HO-1进而调控了铁代谢的机制。中药组改善脂肪肝明显，也降低了HO-1表达，减轻铁沉积。在细胞学试验中，肝细胞脂肪沉积与HO-1表达有关，中剂量中药干预能降低HO-1表达，减轻脂肪沉积。通过大鼠体内体外实验显示，铁沉积在NAFLD发展中具有重要作用，通过直接或间接调节铁代谢，可以改善肝内脂肪沉积进而减轻脂肪肝，为今后临床研发新药物提供了新的思路。