脂肪肝与肝癌严重影响我国人民健康，二者常常伴随发生。部分脂肪肝患者可以发展成脂肪性肝炎，进而导致肝癌发生，但其分子机制不清除。有意义的是本课题组发现和鉴定的LZP (Liver specific ZP domain containing protein)基因在肝癌表达普遍且显著下降，而LZP基因剔出小鼠显示肝脏脂肪沉积，脂质代谢紊乱，提示LZP缺乏导致脂肪肝，进而可能影响肝癌发生、发展。本项目拟基于LZP基因剔出小鼠模型结合人肝癌样本和细胞研究LZP在肝脏脂质代谢过程中的作用、其缺乏对肝癌发生、发展的影响及其分子机制; 在此基础上，探讨LZP或者相关致癌分子机制作为靶向防治肝癌策略的可行性。本项目从LZP缺乏这一独特的角度研究脂肪肝与肝癌的关系，阐述从脂肪肝、脂肪性肝炎发展为肝癌所涉及的病理过程及分子信号通路，将为肝癌发生、发展的机制的理解提供新线索、新思路，也为肝癌防治提供新策略和方法。

Fatty liver, especial nonalcoholic fatty liver disease (NAFLD), may lead to liver injuries ranging from steatosis to steatohepatitis that may progress to cirrhosis and hepatocellular carcinoma (HCC). However, the underlying cellular and molecular mechanisms by which hepatic steatosis contributes to HCC initiation and progression remain obscure. Significantly, LZP (liver-specific zona pellucida domain-containing protein) knockout mice established by our lab exhibit the typical pathological feature of NAFLD with formation of lipid droplets and excess triglyceride (TG), although serum TG and glucose are not elevated in these mice, implying that the LZP-deficient mice could represent a subtype of NAFLD without systemic diseases such as diabetes and obesity. The LZP-deficient mice could provide an ideal animal model for addressing the cellular and molecular mechanisms involved in the course from hepatic steatosis to HCC oncogenesis. Interestingly, LZP, also named oncoprotein induced transcript 3 (OIT3), was first isolated and identified by us from human, mouse and rat livers, and was validated to be specifically expressed in hepatocytes, although very weak in mouse kidney. More interestingly, we confirmed that LZP is obviously downregulated in the majority of HCC specimens, although LZP level cannot affect cell proliferation. Based on these collective data, we propose that LZP could function as a transporter or co-factor in lipid metabolism, in which LZP may transport VLDL (very low density lipoprotein) and LDL (low-density lipoprotein) from hepatocytes to blood; hepatic steatosis occurs in the absence of LZP, and then may progress to steatohepatitis and even HCC in the presence of liver injury and inflammation stimulators, such as alcohol, chemical carcinogens and bacterial toxins such as lipopolysaccharide (LPS). In this project, we hope to confirm the hypothesis by utilizing the LZP-deficient mice, together with in vitro experiments and evaluation in clinical HCC samples. First, to explore the effect of LZP on lipid metabolism, we will observe the subcellular location of lipid droplets in the absence of LZP, and explore the relation between the LZP and known lipid transporters such as apolipoprotein B. Next, to investigate the effect of LZP deficiency on HCC oncogenesis, we will use known chemical carcinogens such as diethylnitrosamine (DEN), LPS and proinflammatory cytokines such as interleukin 6 to treat the LZP-deficient mice, and then evaluate the pathological change and cellular signalling pathways related with steatohepatitis, dysplasia, premalignant lesions and HCC initiation. Finally, we will attempt to treat the mice with steatohepatitis and HCC through regulating LZP and altered signalling molecules due to the deficiency of LZP. In general, the proposal will facilitate the understanding of HCC oncogenesis related to hepatic steatosis and steatohepatitis, and provide the potential strategy for HCC prevention and treatment.