Niemann-Pick Cl like I (NPC1L1) is a protein critical for intestinal cholesterol absorption. The nuclear receptors peroxisome proliferator-activated receptor alpha (PPAR alpha) and liver X receptors (LXR alpha and LXR beta) are major regulators of cholesterol homeostasis and their activation results in a reduced absorption of intestinal cholesterol. The goal of this Study was to define the role of PPAR alpha, and LXR nuclear receptors in the regulation of NPC1L1 gene expression. We show that LXR activators down-regulate APC1L1 mRNA levels in the human enterocyte cell line Caco-2/TC7, whereas PPAR alpha ligands have no effect. Furthermore, NPC1L1 mRNA levels are decreased in vivo, in duodenum of mice treated with the LXR agonist T0901317. In conclusion, the present study identifies NPC1L1 as a novel LXR target gene further Supporting a crucial role of LXR in intestinal cholesterol homeostasis. (c) 2006 Elsevier Inc. All rights reserved.