Gene expression profiling identifies retinoids as potent inducers of macrophage lipid efflux.
Vitamin A and its naturally occurring derivatives 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (ATRA) exert a variety of biological effects including immunomodulation, growth, differentiation, and apoptosis of normal and neoblastic cells. In order to directly study the effects of these retinoids on macrophage gene expression and lipid metabolism, primary human monocytes and in vitro differentiated macrophages were stimulated with beta-carotene, 9-cis RA, and ATRA and global gene expression profiles were analyzed by Affymetrix DNA-microarrays and differentially regulated genes were verified by quantitative TaqMan RT-PCR. Among others, we have identified a strong up-regulation of a cluster of genes involved in cholesterol metabolism including apolipoproteins (apoC-I, apoC-II, apoC-IV, apoE), the scavenger receptor CD36, steroid-27-hydroxylase (CYP27A1), liver X receptor alpha (LXRalpha), and ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Since the CYP27A1 gene displayed the strongest up-regulation on the mRNA level, we cloned various deletion constructs of the promoter region and analyzed the response to retinoids in macrophages. Thereby, a novel retinoic acid-responsive element could be located within 191 bp of the proximal CYP27A1 promoter. To further assess the functional consequences of retinoid receptor action, we carried out phospholipid and cholesterol efflux assays. We observed a strong induction of apoA-I-dependent lipid efflux in stimulated macrophages, implicating an important role for retinoids in cellular functions of macrophages.
Langmann
Thomas
T
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
Liebisch
Gerhard
G
Moehle
Christoph
C
Schifferer
Rainer
R
Dayoub
Rania
R
Heiduczek
Susanne
S
Grandl
Margot
M
Dada
Ashraf
A
Schmitz
Gerd
G
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology; D001053:Apolipoproteins / Q000235:genetics; D018955:CD36 Antigens; D002784:Cholesterol / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000819:agonists; D051116:Receptors, Scavenger; D012176:Retinoids / Q000494:pharmacology / Q000502:physiology*; D019207:beta Carotene / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D018955:CD36 Antigens; D010743:Phospholipids; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid; D051116:Receptors, Scavenger; D012176:Retinoids; D019207:beta Carotene; D002784:Cholesterol