This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/7/682    most recent 01.RES.0000184678.43488.9fv1 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rigamonti, E. Articles by Chinetti-Gbaguidi, G. Search for Related Content PubMed PubMed Citation Articles by Rigamonti, E. Articles by Chinetti-Gbaguidi, G. Related Collections Lipid and lipoprotein metabolism Other Vascular biology Pathophysiology Gene regulation

(Circulation Research. 2005;97:682.)
© 2005 American Heart Association, Inc.

Cellular Biology

Liver X Receptor Activation Controls Intracellular Cholesterol Trafficking and Esterification in Human Macrophages

E. Rigamonti, L. Helin, S. Lestavel, A.L. Mutka, M. Lepore, C. Fontaine, M.A. Bouhlel, S. Bultel, J.C. Fruchart, E. Ikonen, V. Clavey, B. Staels, G. Chinetti-Gbaguidi

From the UR 545 Inserm (E.R., L.H., S.L., M.L., C.F., M.A.B., S.B., J.C.F., V.C., B.S., G.C.-G.), Institut Pasteur de Lille and Université de Lille 2, France; and the Institute of Biotechnology (A.L.M., E.I.), University of Helsinki, Finland.

Correspondence to Bart Staels, UR 545 Inserm, Institut Pasteur de Lille, 1, rue Calmette BP245, 59019 Lille, France. E-mail bart.staels{at}pasteur-lille.fr

Liver X receptors (LXRs) are nuclear receptors that regulate macrophage cholesterol efflux by inducing ATP-binding cassette transporter A1 (ABCA1) and ABCG1/ABCG4 gene expression. The Niemann-Pick C (NPC) proteins NPC1 and NPC2 are located in the late endosome, where they control cholesterol trafficking to the plasma membrane. The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant governing its availability for efflux to extracellular acceptors. Here we investigated the influence of LXR activation on intracellular cholesterol trafficking in primary human macrophages. Synthetic LXR activators increase the amount of free cholesterol in the plasma membrane by inducing NPC1 and NPC2 gene expression. Moreover, ABCA1-dependent cholesterol efflux induced by LXR activators was drastically decreased in the presence of progesterone, which blocks postlysosomal cholesterol trafficking, and reduced when NPC1 and NPC2 mRNA expression was depleted using small interfering RNA. The stimulation of cholesterol mobilization to the plasma membrane by LXRs led to a decrease in cholesteryl ester formation and Acyl–coenzyme A cholesterol acyltransferase-1 activity. These data indicate that LXR activation enhances cholesterol trafficking to the plasma membrane, where it becomes available for efflux, at the expense of esterification, thus contributing to the overall effects of LXR agonists in the control of macrophage cholesterol homeostasis.

Key Words: nuclear receptor • gene regulation • metabolism • atherosclerosis

This article has been cited by other articles:

				C. Fontaine, E. Rigamonti, B. Pourcet, H. Duez, C. Duhem, J.-C. Fruchart, G. Chinetti-Gbaguidi, and B. Staels The Nuclear Receptor Rev-erb{alpha} Is a Liver X Receptor (LXR) Target Gene Driving a Negative Feedback Loop on Select LXR-Induced Pathways in Human Macrophages Mol. Endocrinol., August 1, 2008; 22(8): 1797 - 1811. [Abstract] [Full Text] [PDF]

				E. Rigamonti, G. Chinetti-Gbaguidi, and B. Staels Regulation of Macrophage Functions by PPAR-{alpha}, PPAR-{gamma}, and LXRs in Mice and Men Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1050 - 1059. [Abstract] [Full Text] [PDF]

				C. Buono, Y. Li, S. W. Waldo, and H. S. Kruth Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL J. Lipid Res., November 1, 2007; 48(11): 2411 - 2418. [Abstract] [Full Text] [PDF]

				C. Fontaine, E. Rigamonti, A. Nohara, P. Gervois, E. Teissier, J.-C. Fruchart, B. Staels, and G. Chinetti-Gbaguidi Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages Circ. Res., July 6, 2007; 101(1): 40 - 49. [Abstract] [Full Text] [PDF]

				A. Soro-Paavonen, J. Naukkarinen, M. Lee-Rueckert, H. Watanabe, E. Rantala, S. Soderlund, A. Hiukka, P. T. Kovanen, M. Jauhiainen, L. Peltonen, et al. Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL J. Lipid Res., June 1, 2007; 48(6): 1409 - 1416. [Abstract] [Full Text] [PDF]

				M.-D. Wang, R. S. Kiss, V. Franklin, H. M. McBride, S. C. Whitman, and Y. L. Marcel Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways J. Lipid Res., March 1, 2007; 48(3): 633 - 645. [Abstract] [Full Text] [PDF]

				M. D. Linder, R.-L. Uronen, M. Holtta-Vuori, P. van der Sluijs, J. Peranen, and E. Ikonen Rab8-dependent Recycling Promotes Endosomal Cholesterol Removal in Normal and Sphingolipidosis Cells Mol. Biol. Cell, January 1, 2007; 18(1): 47 - 56. [Abstract] [Full Text] [PDF]

				Y. J. Jiang, B. Lu, P. Kim, P. M. Elias, and K. R. Feingold Regulation of ABCA1 expression in human keratinocytes and murine epidermis J. Lipid Res., October 1, 2006; 47(10): 2248 - 2258. [Abstract] [Full Text] [PDF]

				D. Duffy and D. J. Rader Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport Circulation, February 28, 2006; 113(8): 1140 - 1150. [Full Text] [PDF]