help button home button Endocrine Society Molecular Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on September 7, 2006
Molecular Endocrinology, doi:10.1210/me.2006-0146
A more recent version of this article appeared on December 1, 2006
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
20/12/3165    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Avallone, R.
Right arrow Articles by Tremblay, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Avallone, R.
Right arrow Articles by Tremblay, A.

Submitted on March 31, 2006
Accepted on August 28, 2006

A Growth Hormone-Releasing Peptide that Binds Scavenger Receptor CD36 and Ghrelin Receptor Upregulates ABC Sterol Transporters and Cholesterol Efflux in Macrophages Through a PPAR{gamma}-dependent Pathway

Roberta Avallone, Annie Demers, Amélie Rodrigue-Way, Kim Bujold, Diala Harb, Silvia Anghel, Walter Wahli, Sylvie Marleau, Huy Ong*, and André Tremblay*

Faculty of Pharmacy, Pavillon Jean-Coutu, University of Montreal, Montréal, Québec, H3C 3J7 Canada; Research Center, Ste-Justine Hospital, Montreal, Québec, H3T 1C5 Canada; Center for Integrative Genomics and NCCR Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland; Departments of Biochemistry, and Obstetrics & Gynecology, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1C5 Canada

* To whom correspondence should be addressed. E-mail: huy.ong{at}umontreal.ca or andre.tremblay{at}recherche-ste-justine.qc.ca.

Macrophages play a central role in the pathogenesis of atherosclerosis by accumulating cholesterol through increased uptake of oxidized LDL by scavenger receptor CD36 leading to foam cell formation. Here we demonstrate the ability of hexarelin, a GH releasing peptide, to enhance the expression of ABCA1 and ABCG1 transporters and cholesterol efflux in macrophages. These effects were associated with a transcriptional activation of nuclear receptor PPAR{gamma} in response to binding of hexarelin to CD36 and GHS-R1a, the receptor for ghrelin. The hormone binding domain was not required to mediate PPAR{gamma} activation by hexarelin, and phosphorylation of PPAR{gamma} was increased in THP-1 macrophages treated with hexarelin, suggesting that the response to hexarelin may involve PPAR{gamma} AF-1 activity. However, the activation of PPAR{gamma} by hexarelin did not lead to an increase in CD36 expression, as opposed to LXR{alpha}, suggesting a differential regulation of PPAR{gamma}-targeted genes in response to hexarelin. Chromatin immunoprecipitation assays showed that, in contrast to a PPAR{gamma} agonist, the occupancy of the CD36 promoter by PPAR{gamma} was not increased in THP-1 macrophages treated with hexarelin, while the LXR{alpha} promoter was strongly occupied by PPAR{gamma} in the same conditions. Treatment of apoE-null mice maintained on a lipid-rich diet with hexarelin resulted in a significant reduction in atherosclerotic lesions, concomitant with an enhanced expression of PPAR{gamma} and LXR{alpha} target genes in peritoneal macrophages. Such response was strongly impaired in PPAR{gamma}+/- macrophages, indicating that PPAR{gamma} was required to mediate the effect of hexarelin. These findings provide a novel mechanism by which the beneficial regulation of PPAR{gamma} and cholesterol metabolism in macrophages could be regulated by CD36 and ghrelin receptor downstream effects.
Key words: atherosclerosis • macrophages • nuclear receptors • PPAR • LXR • ABCA1 • ABCG1 • CD36 • GHS-R1a • GHRP • hexarelin • ghrelin • ApoE-knockout mice • oxidized LDL

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ  |  LXRβ  |  LXRα  |  RXRα
Ligands:   22α-Hydroxycholesterol  |  GW 9662  |  Pirinixic acid



This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
A. Tesse, G. Al-Massarani, R. Wangensteen, S. Reitenbach, M. C. Martinez, and R. Andriantsitohaina
Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist, Prevents Microparticle-Induced Vascular Hyporeactivity through the Regulation of Proinflammatory Proteins
J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 539 - 547.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
A. Rodrigue-Way, A. Demers, H. Ong, and A. Tremblay
A Growth Hormone-Releasing Peptide Promotes Mitochondrial Biogenesis and a Fat Burning-Like Phenotype through Scavenger Receptor CD36 in White Adipocytes
Endocrinology, March 1, 2007; 148(3): 1009 - 1018.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. Iantorno, H. Chen, J.-a Kim, M. Tesauro, D. Lauro, C. Cardillo, and M. J. Quon
Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells
Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E756 - E764.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Sanchez, K. Sauve, N. Picard, and A. Tremblay
The Hormonal Response of Estrogen Receptor beta Is Decreased by the Phosphatidylinositol 3-Kinase/Akt Pathway via a Phosphorylation-dependent Release of CREB-binding Protein
J. Biol. Chem., February 16, 2007; 282(7): 4830 - 4840.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2006 by The Endocrine Society