TITLE

HNF4α is a Crucial Modulator of the Cholesterol-Dependent Regulation of NPC1L1

AUTHOR(S)
Yuki Iwayanagi; Tappei Takada; Hiroshi Suzuki
PUB. DATE
May 2008
SOURCE
Pharmaceutical Research;May2008, Vol. 25 Issue 5, p1134
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Abstract Purpose  Niemann-Pick C1-like 1 (NPC1L1) has been identified as a target of ezetimibe and found to be responsible for intestinal cholesterol absorption. Although, it was recently demonstrated that sterol responsive element binding protein 2 (SREBP2) is responsible for the cholesterol-dependent down-regulation of NPC1L1, the molecular mechanism of NPC1L1 expression is not fully understood. In the present study, we examined the involvement of hepatocyte nuclear factor 4α (HNF4α), a key modulator of lipid metabolism, in the transcriptional regulation of human NPC1L1 gene. Methods  Reporter gene assays and EMSAs were performed using human NPC1L1 promoter constructs and the effect of siHNF4α was examined. Results  Transfection of SREBP2 induced the transcriptional activities of NPC1L1 and additional transfection of HNF4α results in a marked stimulation of the activities. Studies with deletion mutants indicated that important elements are located within 264 nt upstream in the human NPC1L1 promoter. In addition, studies with mutations in putative binding sites of HNF4α indicated the existence of binding sites in −209 to −197 and −52 to −40. Moreover, HNF4α knockdown resulted in the reduced expression and regulation by cholesterol. Conclusions  It is concluded that HNF4α plays a crucial role in the expression and regulation of human NPC1L1 gene.
ACCESSION #
32787010

 

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