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

项目摘要 我们使用人iPSC衍生的肝细胞平台鉴定了一个结构相关的家族， 可以减少肝脏产生APOB的小分子。这些小分子 高效，不引起异常脂质积聚，并且具有化学结构 它不同于任何已知的降胆固醇药物。这些化合物有可能 治疗高胆固醇血症和脂肪变性。在本申请中，我们提出将 化合物起作用的分子机制。在初步数据中，我们表明， 化合物抑制人羧酸酯酶1（CES 1）。在三个拟议目标中，我们将： 鉴定化合物与CES 1的结合特征，并使用 晶体学和生物化学测定，ii）使用iPSC-肝细胞来确定性地建立 CES 1在介导（V）化合物的LDL-胆固醇产生中的作用，和iii）确定 所述化合物在降低胆固醇和脂肪变性人源化小鼠模型中的功效。

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.