人肝癌细胞诱导表达ACAT2介导分泌的亚型脂蛋白

Liver plays a central role in cholesterol synthesis, catabolism and excretion. Dysfunction of cholesterol metabolism in liver is closely related to the diseases, such as hepatocellular carcinoma (HCC), diabetes and so on. Our lab has focused on ACAT studies for many years and made very good progresses. Based on our previous studies that have shown ACAT2 gene expression is induced in human HCC, indicating it is an important target of therapy in human HCC, and our recent progresses showing that human HCC cells with induced ACAT2 establish a specific cholesterol metabolic pathway and secrete specific oxysterols-containing lipoproteins, this application focuses on the secreted subtype lipoprotein from human hepatocellular carcinomas cells mediated by the induced ACAT2. By systematically exploring in establishment of systems to separate and determine lipoprotein subtypes, identification of subtype lipoprotein mediated by ACAT2 and their sterols composition, and identification of specific ACAT2-mediated subtype lipoprotein in the plasma from clinical patients, we will establish the methodology systems which can be used to separate and quantify sterols of subtype lipoprotein, and identify the specific subtype lipoprotein from human HCC cells mediated by the induced ACAT2. These will provide novel insights and vital basis for HCC-related studies in targeted drugs, biomarkers, classification and individualized treatment.

肝脏在胆固醇分解、外排等代谢中发挥其它器官不可替代的作用，而其代谢异常与肝癌、胆结石及糖尿病等病变密切关联。我们前期工作发现人肝癌特异诱导表达ACAT2，提示其极有可能成为诊治的重要靶标。本申请项目依据发现成人肝不表达的ACAT2则在肝癌组织被特异诱导高表达（约30％肝癌或约50%晚期肝癌）、表达ACAT2人肝癌细胞株建立胆固醇代谢的新途径并分泌含氧化型胆固醇的特异脂蛋白等基础上，深入研究人肝癌细胞诱导表达ACAT2介导分泌的亚型脂蛋白，主要开展1）亚型脂蛋白分离检测技术系统、2）ACAT2表达细胞分泌的亚型脂蛋白及其固醇类组分、3）临床血样中ACAT2介导分泌的亚型脂蛋白等三方面内容研究，旨在建立能定量亚型脂蛋白中固醇类组分的分离检测技术系统和鉴定出肝癌细胞诱导表达ACAT2介导分泌的亚型脂蛋白，为肝癌相关的靶向药物、生物标志物、分子分型方案、个性化诊治策略等研究提供理论依据和重要基础。

肝脏在胆固醇分解、外排等代谢中发挥其它器官不可替代的作用，而其代谢异常与肝癌、胆结石及糖尿病等病变密切关联。我们前期工作发现人肝癌特异诱导表达ACAT2，提示其极有可能成为诊治的重要靶标。本申请项目依据发现成人肝不表达的ACAT2则在肝癌组织被特异诱导高表达（约30％肝癌或约50%晚期肝癌）、表达ACAT2人肝癌细胞株建立胆固醇代谢的新途径并分泌含氧化型胆固醇的特异脂蛋白等基础上，深入研究人肝癌细胞诱导表达ACAT2介导分泌的亚型脂蛋白，主要开展1）亚型脂蛋白分离检测技术系统、2）ACAT2表达细胞分泌的亚型脂蛋白及其固醇类组分、3）临床血样中ACAT2介导分泌的亚型脂蛋白等三方面内容研究，旨在建立能定量亚型脂蛋白中固醇类组分的分离检测技术系统和鉴定出肝癌细胞诱导表达ACAT2介导分泌的亚型脂蛋白，为肝癌相关的靶向药物、生物标志物、分子分型方案、个性化诊治策略等研究提供理论依据和重要基础。