Chemerin在非酒精性脂肪肝发生过程中的作用机制

Obesity is a high risk factor for nonalcoholic fatty liver disease (NAFLD).We try to understand why NAFLD is so normal in the obese from the perspective of adipokine. It would be helpful for prevention and treatment of NAFLD. Chemerin is a new adipokine identified in 2007, and is expressed highly in patients with NAFLD. we found that Chemerin knockout mice could be induced NAFLD easily than wide type by high fat diet.The roles of Chemerin in NAFLD is not conclusive and the molecular mechanism has not been reported. We try to find the corelation between Chemerin and NAFLD in cells, animals and human tissues.We will explore the roles of Chemerin on fatty acid metabolism in liver cells, the involving Chemerin receptors and signaling pathways in fatty liver cell models. In Chemerin knockout mice, Chemerin receptor knockout mice and Chemerin overexpression transgenic mice, we will study how Chemerin effect on hepacytes, liver Kupffer cells polarization and inflammation. This study can provide deeply understanding on the molecular mechanism of Chemerin on NAFLD, and provide potential targets for prevention and treatment of NAFLD.

肥胖病人易患非酒精性脂肪肝（NAFLD），从脂肪因子的角度理解其原因，可为防治NAFLD提供新视角。脂肪因子Chemerin可以趋化巨噬细胞，在NAFLD病人中高表达，我们前期结果发现Chemerin敲除小鼠更容易高脂诱导脂肪肝，目前Chemerin在NAFLD中的作用没有定论且分子机制未见报道。本课题拟从细胞、动物和人组织标本3个层次研究Chemerin与NAFLD的相关性；在肝细胞脂肪累积模型上探索Chemerin直接调控肝细胞脂代谢以及参与受体和信号通路；在Chemerin以及受体敲除小鼠和过表达Chemerin小鼠中研究Chemerin对肝细胞的直接作用和Chemerin如何影响肝脏枯否细胞（kupffer cell）的极化和肝脏的炎症状态，进而调控NAFLD的发生。通过研究可为深刻理解Chemerin对NAFLD发生的分子机制，为寻找防治NAFLD的分子靶点提供理论基础。

NAFLD的基础病理改变是脂质代谢紊乱和炎症反应，并与其它代谢性疾病密切相关。肥胖病人易患非酒精性脂肪肝（NAFLD），从脂肪因子的角度理解其原因，可为防治NAFLD提供新视角。.本课题从细胞、动物和人组织标本3个层次研究Chemerin与NAFLD的相关性。我们发现脂肪因子Chemerin在NAFLD病人中高表达；高脂饮食条件下，chemerin缺陷小鼠更容易肥胖并伴有NAFLD，肝脏炎症水平增高，糖耐量降低，胰岛素抵抗增强，而在正常饮食条件下，chemerin缺陷小鼠和WT小鼠相比，体重没有差异。体外研究发现，chemerin缺陷的肝脏原代细胞累积更多的脂质，且CD36上调明显。chemerin缺陷小鼠在高脂诱导下，肝脏中促炎的M1型巨噬细胞增加，并且促炎因子的表达明显增加，肝脏处于慢性炎症的状态。为了研究chemerin缺陷促进脂肪肝的分子机制，我们在高脂喂养条件下，发现通过尾静脉注射CD36敲低腺病毒能逆转chemerin缺陷所导致的NAFLD。进一步研究发现，chemerin缺失下调ERK的磷酸化，刺激PPARγ高表达，进而引起CD36表达上调，促进肝细胞对脂质的摄取。.通过本研究可为深刻理解脂肪因子Chemerin对NAFLD发生的分子机制，为寻找防治NAFLD的分子靶点提供理论依据。