脂肪组织赖氨酰氧化酶对非酒精性脂肪肝的作用研究

非酒精性脂肪性肝病（Non-alcoholic fatty liver disease，NAFLD）是全球最常见慢性肝病，肥胖是其最主要危险因素。肥胖时，脂肪组织胰岛素抵抗促进脂解和游离脂肪酸释放入肝及脂肪因子分泌谱改变是肥胖相关NAFLD发生的主要机制。我们发现脂肪组织赖氨酰氧化酶(Lysyl Oxidase, Lox)能感知机体能量变化和提高脂肪组织胰岛素敏感性；而脂肪细胞分泌的赖氨酰氧化酶亦能进入肝源性细胞调控脂代谢。在此基础上，我们认为在不同能量状态下，脂肪组织赖氨酰氧化酶通过调控脂肪组织胰岛素敏感性和游离脂肪酸释放及自身分泌入肝两种方式调节肝脏脂质的堆积和NAFLD发生。我们将利用动物模型和细胞模型，研究脂肪组织赖氨酰氧化酶调控肝脏脂代谢和NAFLD发生的具体机制。该研究可为提高脂肪组织胰岛素敏感性和治疗NAFLD提供新的分子靶点，也将为脂肪组织与肝脏间对话研究提供新的理论依据。

The obesity is closely associated with the rising prevalence and severity of non-alcoholic fatty liver disease (NAFLD). In obesity, both increased afflux of adipose tissue-derived free fatty acids（FFAs） to the liver due to a failure of insulin-mediated suppression of lipolysis and the alteration of adipose tissue-derived adipokines contribute to the development of NAFLD. Herein, we have found that lysyl oxidase (Lox), which is mostly synthesized and secreted from adipocytes, functions as a potent energy sensor and insulin sensitizer. Notably, we have also found that Lox can be trafficked from adipocytes to HepG2 cells behaving nearly the same as human hepatocytes in vitro and regulate hepatic lipid metabolism. These studies have laid an important foundation for our continued understanding of how adipocyte-derived Lox modulate liver metabolism. We will combine both the cellular and animal models to further investigate whether adipose tissue-derived Lox regulate lipolysis and FFAs release from adipose tissue through modulating insulin sensitivity or is transferred to liver and acts directly on liver metabolism. This work might offer new insights into the communication between adipose tissue and liver and deepen our understanding of the molecular mechanism of NAFLD. Our studies will also open up new opportunities to identify Lox as a therapeutic target for increasing insulin sensitivity of adipose tissue and the treatment of NAFLD.