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J. Biol. Chem., Vol. 283, Issue 34, 22930-22941, August 22, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/34/22930    most recent M801408200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Google Scholar Articles by Zhu, X. Articles by Parks, J. S. PubMed PubMed Citation Articles by Zhu, X. Articles by Parks, J. S. Social Bookmarking                      What's this?

Increased Cellular Free Cholesterol in Macrophage-specific Abca1 Knock-out Mice Enhances Pro-inflammatory Response of Macrophages^*

Xuewei Zhu, Ji-Young Lee, Jenelle M. Timmins, J. Mark Brown, Elena Boudyguina, Anny Mulya, Abraham K. Gebre, Mark C. Willingham, Elizabeth M. Hiltbold^¶, Nilamadhab Mishra^||, Nobuyo Maeda^**, and John S. Parks¹

From the Departments of Pathology/Lipid Sciences, Pathology/Tumor Biology, ^¶Microbiology and Immunology, and ^||Internal Medicine/Rheumatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 and the ^**Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

Macrophage-specific Abca1 knock-out (Abca1^–M/–M) mice were generated to determine the role of macrophage ABCA1 expression in plasma lipoprotein concentrations and the innate immune response of macrophages. Plasma lipid and lipoprotein concentrations in chow-fed Abca1^–M/–M and wild-type (WT) mice were indistinguishable. Compared with WT macrophages, Abca1^–M/–M macrophages had a >95% reduction in ABCA1 protein, failed to efflux lipid to apoA-I, and had a significant increase in free cholesterol (FC) and membrane lipid rafts without induction of endoplasmic reticulum stress. Lipopolysaccharide (LPS)-treated Abca1^–M/–M macrophages exhibited enhanced expression of pro-inflammatory cytokines and increased activation of the NF-B and MAPK pathways, which could be diminished by silencing MyD88 or by chemical inhibition of NF-B or MAPK. In vivo LPS injection also resulted in a higher pro-inflammatory response in Abca1^–M/–M mice compared with WT mice. Furthermore, cholesterol depletion of macrophages with methyl-β-cyclodextrin normalized FC content between the two genotypes and their response to LPS; cholesterol repletion of macrophages resulted in increased cellular FC accumulation and enhanced cellular response to LPS. Our results suggest that macrophage ABCA1 expression may protect against atherosclerosis by facilitating the net removal of excess lipid from macrophages and dampening pro-inflammatory MyD88-dependent signaling pathways by reduction of cell membrane FC and lipid raft content.

Received for publication, February 21, 2008 , and in revised form, June 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL49373, HL54176, and AT27820 (to J. S. P.) and HL07115 (cardiovascular pathology training grant; to J. M. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures," Figs. S1–S3, and Table S1.

¹ To whom correspondence should be addressed: Dept. of Pathology/Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. Tel.: 336-716-2145; Fax: 336-716-6279; E-mail: jparks{at}wfubmc.edu.

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