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Papers In Press, published online ahead of print December 16, 2004
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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 PPAR
Revised on November 23, 2004
Accepted on December 9, 2004
Reduced cholesterol absorption upon PPAR
activation coincides with decreased intestinal expression of NPC1L1
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 PPAR
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, PPAR
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- PPAR
activation is associated with elevated plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPAR
is a promising target for drugs aimed to treat or prevent atherosclerosis.
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