HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M400400-JLR200v1 46/3/526    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van der Veen, J. N. Articles by Kuipers, F. Search for Related Content PubMed PubMed Citation Articles by van der Veen, J. N. Articles by Kuipers, F. Social Bookmarking                      What's this?

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 Veen^1,2,*, Janine K. Kruit^2,*, 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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Tancevski, A. Wehinger, E. Demetz, P. Eller, K. Duwensee, J. Huber, K. Hochegger, W. Schgoer, C. Fievet, F. Stellaard, et al. Reduced Plasma High-Density Lipoprotein Cholesterol in Hyperthyroid Mice Coincides with Decreased Hepatic Adenosine 5'-Triphosphate-Binding Cassette Transporter 1 Expression Endocrinology, July 1, 2008; 149(7): 3708 - 3712. [Abstract] [Full Text] [PDF]

				T.-L. Yue, S. S. Nerurkar, W. Bao, B. M. Jucker, L. Sarov-Blat, K. Steplewski, E. H. Ohlstein, and R. N. Willette In Vivo Activation of Peroxisome Proliferator-Activated Receptor-{delta} Protects the Heart from Ischemia/Reperfusion Injury in Zucker Fatty Rats J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 466 - 474. [Abstract] [Full Text] [PDF]

				H. M. de Vogel-van den Bosch, N. J. W. de Wit, G. J. E. J. Hooiveld, H. Vermeulen, J. N. van der Veen, S. M. Houten, F. Kuipers, M. Muller, and R. van der Meer A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1171 - G1180. [Abstract] [Full Text] [PDF]

				A. B. Weinglass, M. G. Kohler, E. O. Nketiah, J. Liu, W. Schmalhofer, A. Thomas, B. Williams, L. Beers, L. Smith, M. Hafey, et al. Madin-Darby Canine Kidney II Cells: A Pharmacologically Validated System for NPC1L1-Mediated Cholesterol Uptake Mol. Pharmacol., April 1, 2008; 73(4): 1072 - 1084. [Abstract] [Full Text] [PDF]

				Y. Liu, H. van Goor, R. Havinga, J. F. W. Baller, V. W. Bloks, F. R. van der Leij, P. J. J. Sauer, F. Kuipers, G. Navis, and M. H. de Borst Neonatal dexamethasone administration causes progressive renal damage due to induction of an early inflammatory response Am J Physiol Renal Physiol, April 1, 2008; 294(4): F768 - F776. [Abstract] [Full Text] [PDF]

				U. Riserus, D. Sprecher, T. Johnson, E. Olson, S. Hirschberg, A. Liu, Z. Fang, P. Hegde, D. Richards, L. Sarov-Blat, et al. Activation of Peroxisome Proliferator-Activated Receptor (PPAR){delta} Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men Diabetes, February 1, 2008; 57(2): 332 - 339. [Abstract] [Full Text] [PDF]

				M. A. Valasek, S. L. Clarke, and J. J. Repa Fenofibrate reduces intestinal cholesterol absorption via PPAR{alpha}-dependent modulation of NPC1L1 expression in mouse J. Lipid Res., December 1, 2007; 48(12): 2725 - 2735. [Abstract] [Full Text] [PDF]

				H. E. Hollingshead, R. L. Killins, M. G. Borland, E. E. Girroir, A. N. Billin, T. M. Willson, A. K. Sharma, S. Amin, F. J. Gonzalez, and J. M. Peters Peroxisome proliferator-activated receptor- /{delta} (PPAR /{delta}) ligands do not potentiate growth of human cancer cell lines Carcinogenesis, December 1, 2007; 28(12): 2641 - 2649. [Abstract] [Full Text] [PDF]

				B. M. Jucker, D. Yang, W. M. Casey, A. R. Olzinski, C. Williams, S. C. Lenhard, J. J. Legos, C. T. Hawk, S. K. Sarkar, and S. J. Newsholme Selective PPAR{delta} agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1256 - E1264. [Abstract] [Full Text] [PDF]

				M. Schupp, J. C. Curtin, R. J. Kim, A. N. Billin, and M. A. Lazar A Widely Used Retinoic Acid Receptor Antagonist Induces Peroxisome Proliferator-Activated Receptor-{gamma} Activity Mol. Pharmacol., May 1, 2007; 71(5): 1251 - 1257. [Abstract] [Full Text] [PDF]

				J. N. van der Veen, R. Havinga, V. W. Bloks, A. K. Groen, and F. Kuipers Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor {alpha} J. Lipid Res., February 1, 2007; 48(2): 337 - 347. [Abstract] [Full Text] [PDF]

				S. N. Mathur, K. R. Watt, and F. J. Field Regulation of intestinal NPC1L1 expression by dietary fish oil and docosahexaenoic acid J. Lipid Res., February 1, 2007; 48(2): 395 - 404. [Abstract] [Full Text] [PDF]

				D. L. Sprecher, C. Massien, G. Pearce, A. N. Billin, I. Perlstein, T. M. Willson, D. G. Hassall, N. Ancellin, S. D. Patterson, D. C. Lobe, et al. Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor {delta} Agonist Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 359 - 365. [Abstract] [Full Text] [PDF]

				W. A. Alrefai, F. Annaba, Z. Sarwar, A. Dwivedi, S. Saksena, A. Singla, P. K. Dudeja, and R. K. Gill Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: role of sterol regulatory element binding protein 2 Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G369 - G376. [Abstract] [Full Text] [PDF]

				F. Lalloyer, C. Fievet, S. Lestavel, G. Torpier, J. van der Veen, V. Touche, S. Bultel, S. Yous, F. Kuipers, R. Paumelle, et al. The RXR Agonist Bexarotene Improves Cholesterol Homeostasis and Inhibits Atherosclerosis Progression in a Mouse Model of Mixed Dyslipidemia Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2731 - 2737. [Abstract] [Full Text] [PDF]

				T. Plosch, J. N. van der Veen, R. Havinga, N. C. A. Huijkman, V. W. Bloks, and F. Kuipers Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice Am J Physiol Gastrointest Liver Physiol, September 1, 2006; 291(3): G414 - G423. [Abstract] [Full Text] [PDF]

				T. Plosch, J. K. Kruit, V. W. Bloks, N. C. A. Huijkman, R. Havinga, G. S. M. J. E. Duchateau, Y. Lin, and F. Kuipers Reduction of Cholesterol Absorption by Dietary Plant Sterols and Stanols in Mice Is Independent of the Abcg5/8 Transporter J. Nutr., August 1, 2006; 136(8): 2135 - 2140. [Abstract] [Full Text] [PDF]