Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms

Significance The Aster proteins are transporters that move cholesterol between the plasma membrane and the ER. Here, we develop and characterize small molecules that selectively inhibit one or more Aster proteins. Importantly, we identify compounds that block Aster-mediated cholesterol transport without interfering with other sterol regulatory proteins, including NPC1 and SREBP2. Cell studies reveal that inhibition of Aster function by small molecules blocks the movement of LDL-derived cholesterol from the plasma membrane to the ER, thus positioning the nonvesicular Aster pathway downstream of the NPC1 vesicular pathway in the movement of LDL-derived cholesterol.