Abstract
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. 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 led to a dose-dependent increase of Angptl3 mRNA. Analysis of the DNA sequence just 5' of the Angptl3 transcriptional start site revealed the presence of several potential transcription factor binding sites, including that for LXR. When transfected into HepG2 cells, the promoter activity of Angptl3 was significantly induced by LXR- or retinoid X receptor-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.
Highlights
Angiopoietins are members of the vascular endothelial growth factor family
To determine if expression of angiopoietin-like protein 3 (Angptl3) mRNA may be subject to regulation in response to perturbations of cholesterol homeostasis, mice were fed for 7 days with a normal chow diet or with the same supplemented with 4% of cholesterol
In light of the potential importance of Angptl3 in lipid metabolism [3], we studied the transcriptional regulation of Angptl3
Summary
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. Angiopoietin-like protein 3 (Angptl3), was previously found to be expressed in a liver specific manner [2], and more recently, it was found to play an important role in the regulation of lipid metabolism [3]. Administration or overexpression of Angptl in mice elicited a rapid increase in circulating levels of plasma cholesterol, triglycerides (TG), and non-esterified fatty acids [3] While these studies revealed a role of Angptl in lipid metabolism, they did not address the molecular mechanism by which a hyperlipidemic response was mediated by Angptl. To determine if Angptl might be such a factor, we stud-
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