J. Lipid Res.
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A more recent version of this article appeared on March 1, 2005

Papers In Press, published online ahead of print December 16, 2004
J. Lipid Res., doi:10.1194/jlr.M400400-JLR200
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Submitted on October 12, 2004
Revised on November 23, 2004
Accepted on December 9, 2004

Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1

Jelske N. van der Veen, Janine K. Kruit, Rick Havinga, Julius F. W. Baller, Giovanna Chimini, Sophie Lestavel, Bart Staels, Pieter H. E. Groot, Albert K. Groen, and Folkert Kuipers

Laboratory of Pediatrics, University Hospital Groningen, Groningen 9713 GZ

Corresponding Author: j.n.van.der.veen{at}med.rug.nl

Objectives- Peroxisome proliferator-activated receptors (PPARs) control transcription of genes involved in lipid metabolism. Activation of PPARdelta may have anti-atherogenic effects through elevation of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues towards the liver for removal via bile and feces. Methods and results- Effects of PPARdelta activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1-/-) mice that lack HDL. Treatment with GW610742 resulted in a ~50% increase of plasma HDL-cholesterol in wild-type mice, whereas plasma cholesterol levels remained extremely low in Abca1-/- mice. Yet, biliary cholesterol secretion rates were similar in untreated wild-type and Abca1-/- mice and unaltered upon treatment. Unexpectedly, PPARdelta activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1, Abcg5, Abcg8 and HMG-CoA reductase expression. Moreover, GW610742 treatment resulted in a 43% reduction of fractional cholesterol absorption in wild-type mice, coinciding with a significantly reduced expression of the cholesterol absorption protein Niemann-Pick C1 Like 1 (Npc1l1) in the intestine. Conclusions- PPARdelta activation is associated with elevated plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPARdelta is a promising target for drugs aimed to treat or prevent atherosclerosis.


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