Human NPC1L1 Expression is Positively Regulated by PPARα
Purpose Niemann-Pick C1-like 1 (NPC1L1), a pharmacological target of ezetimibe, is responsible for cholesterol absorption in enterocytes
and hepatocytes. In the present study, the involvement of peroxisome proliferator-activated receptor α (PPARα) and its cofactor,
PPARγ coactivator 1α (PGC1α) in the transcriptional regulation of human NPC1L1 was analyzed.
Methods Reporter gene assays and electrophoretic mobility shift assays (EMSAs) were performed with the 5′-flanking region of the human
NPC1L1 gene and the effect of siPPARα was examined.
Results PPARα-mediated transactivation was observed with human NPC1L1 promoter constructs. Detailed analyses using deletion- and mutated-promoter
constructs revealed the presence of a functional PPARα-response element (PPRE) upstream of the human NPC1L1 gene (−846/−834),
a direct binding of PPARα and RXRα to which was confirmed by EMSAs. Moreover, PPARα-specific knockdown resulted in a significant
decrease in the endogenous expression of NPC1L1 mRNA and protein in human-derived HepG2 cells. Furthermore, cotransfection
of PGC1α stimulated the SREBP2/HNF4α- and PPARα/RXRα-mediated activation of the human NPC1L1 promoter.
Conclusions We found that PPARα positively regulates human NPC1L1 transcription via direct binding to a PPRE. Additionally, PGC1α stimulates
the SREBP2/HNF4α- and PPARα/RXRα-mediated transactivation of human NPC1L1. These findings may provide new insights into the
close relationship of glucose, fatty acids and cholesterol homeostasis.