Human NPC1L1 expression is positively regulated by PPARα.
Pharm Res
; 28(2): 405-12, 2011 Feb.
Article
in En
| MEDLINE
| ID: mdl-20953676
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
PPAR alpha
/
PPAR gamma
/
Intestinal Mucosa
/
Membrane Proteins
Limits:
Humans
Language:
En
Journal:
Pharm Res
Year:
2011
Document type:
Article
Affiliation country: