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Originally published In Press as doi:10.1194/jlr.M400400-JLR200 on December 16, 2004
Journal of Lipid Research, Vol. 46, 526-534, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology
Reduced cholesterol absorption upon PPAR activation coincides with decreased intestinal expression of NPC1L1
Jelske N. van der Veen1,2,*,
Janine K. Kruit2,*,
Rick Havinga*,
Julius F. W. Baller*,
Giovanna Chimini ,
Sophie Lestavel ,
Bart Staels,
Pieter H. E. Groot**,
Albert K. Groen and
Folkert Kuipers*
* Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, Groningen, The Netherlands
Centre de Immunology, Marseille, France
Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale, Departement d'Atherosclerose, Institut Pasteur de Lille, Lille, France
** Atherosclerosis Department, GlaxoSmithKline Pharmaceuticals, Stevenage, United Kingdom
Department of Experimental Hepatology, Academic Medical Center, Amsterdam, The Netherlands
1 To whom correspondence should be addressed. e-mail: j.n.van.der.veen{at}med.rug.nl
Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPAR may have antiatherogenic effects through the increase of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues toward the liver for removal via bile and feces. Effects of PPAR activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1–/–) mice that lack HDL. Treatment with GW610742 resulted in an  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 3-hydroxy-3-methylglutaryl-coenzyme A 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. PPAR activation is associated with increased 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.
Abbreviations: Abca1–/–, Abca1-deficient; FPLC, fast-protein liquid chromatography; Hmgr, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Mdr2, multidrug resistance P-glycoprotein 2; NPC1L1, Niemann-Pick C1-like 1; Pdk4, pyruvate dehydrogenase kinase isoenzyme 4; PPAR, peroxisome proliferator-activated receptor; RCT, reverse cholesterol transport; Sr-b1, scavenger receptor B1 Supplementary key words Niemann-Pick C1-like 1 • peroxisome proliferator-activated receptor • nuclear receptors • high density lipoprotein-cholesterol
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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
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