NDLI: Human NPC1L1 Expression is Positively Regulated by PPARα

Content Provider	Springer Nature Link
Author	Iwayanagi, Yuki Takada, Tappei Tomura, Fumiya Yamanashi, Yoshihide Terada, Tomohiro Inui, Ken ichi Suzuki, Hiroshi
Copyright Year	2010
Abstract	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.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.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.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.
Starting Page	405
Ending Page	412
Page Count	8
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	28
Issue Number	2
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2010-10-16
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Biomedical Engineering Medical Law Biochemistry Pharmacy Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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