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Papers In Press, published online ahead of print October 16, 2002
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Submitted on September 16, 2002
Atheroscleorsis and Endocrinology, Merck Research Laboratories, Rahway, NJ 07065
Corresponding Author: tianquan_cai{at}merck.com
Angiopoietins are members of the vascular endothelial growth factor family. One family member, angiopoietin-like protein 3 (Angptl3), was recently shown to be predominantly expressed in the liver, and to play an important role in regulating lipid metabolism. In this study, we show that the Angptl3 gene is a direct target of the liver X receptor, LXR. Mice fed a high cholesterol diet exhibited a significant increase in Angptl3 expression in the liver, suggesting that Angptl3 is regulated in response to perturbations of cholesterol homeostasis. Oral administration to mice of T0901317, a synthetic LXR-selective agonist, increases levels of plasma lipids and Angptl3 mRNA in the liver. Treatment of HepG2 cells with LXR selective agonists, such as 22(R)-hydroxycholesterol and T0901317, led to a dose-dependent increase of Angptl3 mRNA, suggesting that LXR agonists can regulate Angptl3 by acting directly on the hepatocytes. Analysis of the DNA sequence just 5' of the Angptl3 transcriptional start site revealed the presence of several potential transcription factor binding sites including those for LXR, HNF-1, HNF-4, NFkB and C/EBP. With these data we developed an Angptl3 promoter construct assay. When transfected into HepG2 cells, the promoter activity of Angptl3 was significantly induced by LXR- or RXR-selective agonists. Mutation of the predicted LXR binding site (DR4 element) completely abolished the LXR agonist-mediated activation of the promoter. Together, these studies show that Angptl3 is transcriptionally regulated by LXR, and reveals a novel mechanism by which LXR may regulate lipid metabolism.
Revised on October 16, 2002
Accepted on October 2, 2002
Regulation of the angiopoietin-like protein 3 (Angptl3) gene by LXR
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