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

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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.