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Impaired trafficking of cholesterol to or from the endoplasmic reticulum (ER) has been implicated in many disease states including Neimann-Pick disease type C (NPC), Alzheimers disease and atherosclerosis. U-18666A is a cell permeable drug that inhibits cholesterol trafficking. It inhibits cholesterol transport from late endosomes/lysosomes to the endoplasmic reticulum (ER), but not cholesterol transport to the plasma membrane as demonstrated in many cell types including macrophages, primary cortical neurons and primary fibroblasts. In macrophages, micromolar concentrations of U-18666A inhibit multiple pathways of cholesterol trafficking from late endosomes, whereas nanomolar concentrations impair cholesterol trafficking to the ER, a response similar to that found in NPC. U-18666A inhibits oxidosqualene cyclase at high (>0.5 mM) concentrations and oral doses (10 mg/kg) induces cataracts in rats.
