JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M502761200 on April 6, 2005

J. Biol. Chem., Vol. 280, Issue 23, 22212-22221, June 10, 2005
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
280/23/22212    most recent
M502761200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Argmann, C. A.
Right arrow Articles by Huff, M. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Argmann, C. A.
Right arrow Articles by Huff, M. W.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition

A ROLE FOR RhoA IN ABCA1-MEDIATED CHOLESTEROL EFFLUX*

Carmen A. Argmann{ddagger}§, Jane Y. Edwards{ddagger}, Cynthia G. Sawyez{ddagger}, Caroline H. O'Neil{ddagger}, Robert A. Hegele{ddagger}§||**, J. Geoffrey Pickering{ddagger}§||, and Murray W. Huff{ddagger}§||{ddagger}{ddagger}

From the {ddagger}Robarts Research Institute Vascular Biology Group and the Departments of Medicine and §Biochemistry, the University of Western Ontario, London, Ontario N6A 5K8, Canada

The cholesterol biosynthetic pathway produces numerous signaling molecules. Oxysterols through liver X receptor (LXR) activation regulate cholesterol efflux, whereas the non-sterol mevalonate metabolite, geranylgeranyl pyrophosphate (GGPP), was recently demonstrated to inhibit ABCA1 expression directly, through antagonism of LXR and indirectly through enhanced RhoA geranylgeranylation. We used HMG-CoA reductase inhibitors (statins) to test the hypothesis that reduced synthesis of mevalonate metabolites would enhance cholesterol efflux and attenuate foam cell formation. Preincubation of THP-1 macrophages with atorvastatin, dose dependently (1–10 µM) stimulated cholesterol efflux to apolipoprotein AI (apoAI, 10–60%, p < 0.05) and high density lipoprotein (HDL3) (2–50%, p < 0.05), despite a significant decrease in cholesterol synthesis (2–90%). Atorvastatin also increased ABCA1 and ABCG1 mRNA abundance (30 and 35%, p < 0.05). Addition of mevalonate, GGPP or farnesyl pyrophosphate completely blocked the statin-induced increase in ABCA1 expression and apoAI-mediated cholesterol efflux. A role for RhoA was established, because two inhibitors of Rho protein activity, a geranylgeranyl transferase inhibitor and C3 exoenzyme, increased cholesterol efflux to apoAI (20–35%, p < 0.05), and macrophage expression of dominant-negative RhoA enhanced cholesterol efflux to apoAI (20%, p < 0.05). In addition, atorvastatin increased the RhoA levels in the cytosol fraction and decreased the membrane localization of RhoA. Atorvastatin treatment activated peroxisome proliferator activated receptor {gamma} and increased LXR-mediated gene expression suggesting that atorvastatin induces cholesterol efflux through a molecular cascade involving inhibition of RhoA signaling, leading to increased peroxisome proliferator activated receptor {gamma} activity, enhanced LXR activation, increased ABCA1 expression, and cholesterol efflux. Finally, statin treatment inhibited cholesteryl ester accumulation in macrophages challenged with atherogenic hypertriglyceridemic very low density lipoproteins indicating that statins can regulate foam cell formation.

Received for publication, March 14, 2005

* This work was supported by Grant MT 8014 (to M. W. H.) and a studentship from the Canadian Institutes for Health Research (to C. A. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| Career Investigators of the Heart and Stroke Foundation of Ontario.

** Holds a Canada Research Chair (Tier I) in Human Genetics.

{ddagger}{ddagger} To whom correspondence should be addressed: Robarts Research Institute, Rm. 4-16, 100 Perth Dr., London, Ontario, Canada, N6A 5K8. Tel.: 519-663-3793; Fax: 519-663-3112; E-mail: mhuff{at}uwo.ca.


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


This article has been cited by other articles:


Home page
 J. Immunol.Home page
K. Smoak, J. Madenspacher, S. Jeyaseelan, B. Williams, D. Dixon, K. R. Poch, J. A. Nick, G. S. Worthen, and M. B. Fessler
Effects of Liver X Receptor Agonist Treatment on Pulmonary Inflammation and Host Defense
J. Immunol., March 1, 2008; 180(5): 3305 - 3312.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
R. Paumelle and B. Staels
Peroxisome Proliferator-Activated Receptors Mediate Pleiotropic Actions of Statins
Circ. Res., May 25, 2007; 100(10): 1394 - 1395.
[Full Text] [PDF]

Home page
 Circ. Res.Home page
M. Yano, T. Matsumura, T. Senokuchi, N. Ishii, Y. Murata, K. Taketa, H. Motoshima, T. Taguchi, K. Sonoda, D. Kukidome, et al.
Statins Activate Peroxisome Proliferator-Activated Receptor {gamma} Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase-Dependent Cyclooxygenase-2 Expression in Macrophages
Circ. Res., May 25, 2007; 100(10): 1442 - 1451.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. Beyea, C. L. Heslop, C. G. Sawyez, J. Y. Edwards, J. G. Markle, R. A. Hegele, and M. W. Huff
Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol
J. Biol. Chem., February 23, 2007; 282(8): 5207 - 5216.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
N. M. White, D. Jiang, J. D. Burgess, I. R. Bederman, S. F. Previs, and T. J. Kelley
Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis
Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L476 - L486.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Abildayeva, P. J. Jansen, V. Hirsch-Reinshagen, V. W. Bloks, A. H. F. Bakker, F. C. S. Ramaekers, J. de Vente, A. K. Groen, C. L. Wellington,, F. Kuipers, et al.
24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux
J. Biol. Chem., May 5, 2006; 281(18): 12799 - 12808.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
I. Zanotti, F. Poti, E. Favari, K. R. Steffensen, J.-A. Gustafsson, and F. Bernini
Pitavastatin Effect on ATP Binding Cassette A1-Mediated Lipid Efflux from Macrophages: Evidence for Liver X Receptor (LXR)-Dependent and LXR-Independent Mechanisms of Activation by cAMP
J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 395 - 401.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.