Inhibition of hepatic (V)LDL production by a novel antagonist of carboxyl esterase 1

项目摘要 我们使用人IPSC来源的肝细胞平台来鉴定一个结构上相关的家族 可以减少肝脏产生载脂蛋白的小分子。这些小分子 都是高效的，不会引起异常的脂肪堆积，并具有化学结构 这与任何已知的降胆固醇药物不同。这类化合物有可能 治疗高胆固醇血症和脂肪变性。在当前应用程序中，我们建议定义 化合物发挥作用的分子机制。在初步数据中，我们表明 化合物抑制人类羧酸酯酶1(CES1)。在提出的三个目标中，我们将i) 确定化合物与CES1的结合特性，并使用 结晶学和生化分析，II)使用IPSC-肝细胞来确定 CES1在化合物产生(V)低密度脂蛋白-胆固醇中的作用，以及iii)确定 化合物在降低胆固醇和脂肪变性方面的功效人源化小鼠模型。

Project Summary We used a human iPSC-derived hepatocyte platform to identify a family of structurally related small molecules that can reduce the production of APOB by the liver. These small molecules are highly effective, do not cause abnormal lipid accumulation, and have a chemical structure that is distinct from any known cholesterol lowering drug. Such compounds have the potential to treat hypercholesterolemia and steatosis. In the current application we propose to define the molecular mechanisms through which the compounds act. In preliminary data we show that the compounds inhibit human carboxylesterase 1 (CES1). In the three proposed aims we will i) identify the binding characteristics of the compounds to CES1 and define their specificity using crystallography and biochemical assays, ii) use iPSC-hepatocytes to definitively establish the role of CES1 in mediating (V)LDL-cholesterol production by the compounds, and iii) determine the efficacy of the compounds in lowering cholesterol and steatosis humanized mouse models.