The molecular processes involved in cholesterol uptake from the intestinal lumen by enterocytes are not well understood. Ezetimibe, a cholesterol absorption inhibitor, prevents this specific transport activity. To gain a better understanding of ezetimibe function and how cholesterol absorption is controlled, a series of microarray studies were conducted. The experiments focused on two aspects of intestinal cholesterol absorption: How intestinal gene expression in mice is affected by ezetimibe treatment, and can tissue specific expression profiling be used to identify components of the cholesterol uptake pathway. In the microarray studies, mice fed a high cholesterol/cholate diet had an intestinal gene expression signature that was anticorrelated with that of animals only receiving ezetimibe, which caused upregulation of genes involved in cholesterol synthesis. Since cholesterol uptake occurs predominantly in the duodenum and jejunum, expression profiling of these tissues was performed and compared with other tissues to identify genes specifically involved in this uptake function. Among the genes identified from this dataset was NPC1L1. Mouse knockout studies conducted concurrently with the microarray experiment identified NPC1L1 as a candidate gene for the molecular target of ezetimibe with NPC1L1 deficient mice demonstrating a severe deficiency in cholesterol absorption and unresponsiveness to ezetimibe (Altmann, et al. 2004 Science, 303:1149-1150.). Thus, the microarray experiments showed that NPC1L1 was not only expressed in the appropriate tissue types for intestinal cholesterol absorption, which is consistent with the mouse knockout data, but ezetimibe treatment can affect the expression of cholesterol synthesis genes.
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