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Am J Physiol Gastrointest Liver Physiol (September 28, 2006). doi:10.1152/ajpgi.00306.2006
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Submitted on July 11, 2006
Accepted on September 24, 2006

Modulation of Human Niemann-Pick C1 like 1 Gene Expression by Sterol: Role of Sterol Regulatory Element Binding Protein-2

Waddah Alrefai1*, Fadi Annaba2, Zaheer Sarwar2, Alka Dwivedi2, Seema Saksena2, Amika Singla2, Pradeep K. Dudeja3, and Ravinder Gill1

1 University of Illinois at Chicago, United States
2 Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
3 Dept. Medicine, WSVA Med. Ctr., U. Illinois at Chicago, Chicago, Illinois, United States

* To whom correspondence should be addressed. E-mail: walrefai{at}uic.edu.

Niemann-Pick C1-like 1 (NPC1L1) is an essential intestinal component of cholesterol absorption. However, little is known about the molecular regulation of intestinal NPC1L1 expression and promoter activity. We demonstrate that human NPC1L1 mRNA expression was significantly decreased by 25-hydroxycholseterol but increased in response to cellular cholesterol depletion achieved by incubation with Mevinolin (inhibitor of HMG-CoA reductase) in human intestinal Caco2 cells. We also show that a -1741/+59 fragment of NPC1L1 gene demonstrated high promoter activity in Caco2 cells that was reduced by 25-HCH and stimulated by cholesterol depletion. Interestingly, we show that NPCL1L1 promoter is remarkably transactivated by the overexpression of the Sterol Regulatory Element Binding Protein SREBP-2 suggesting its involvement in sterol-induced alteration in NPC1L1 promoter activity. Finally, we have identified two putative (Sterol Response Elements) SREs in human NPC1L1 promoter and established their essential roles in mediating the effects of cholesterol on the promoter activity. Our studies demonstrate the modulation of human NPC1L1 expression and promoter activity by cholesterol in SREBP-2-dependent mechanism.




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