Liver X receptor-mediated induction of cholesteryl ester transfer protein expression is selectively impaired in inflammatory macrophages.
OBJECTIVE
Cholesteryl ester transfer protein (CETP) is a target gene for the liver X receptor (LXR). The aim of this study was to further explore this regulation in the monocyte-macrophage lineage and its modulation by lipid loading and inflammation, which are key steps in the process of atherogenesis.


RESULTS
Exposure of bone marrow-derived macrophages from human CETP transgenic mice to the T0901317 LXR agonist increased CETP, PLTP, and ABCA1 mRNA levels. T0901317 also markedly increased CETP mRNA levels and CETP production in human differentiated macrophages, whereas it had no effect on CETP expression in human peripheral blood monocytes. In inflammatory mouse and human macrophages, LXR-mediated CETP gene upregulation was inhibited, even though ABCA1, ABCG1, and SREBP1c inductions were maintained. The inhibition of CETP gene response to LXR agonists in inflammatory cells was independent of lipid loading (ie, oxidized LDL increased CETP production in noninflammatory macrophages with a synergistic effect of synthetic LXR agonists).


CONCLUSIONS
LXR-mediated induction of human CETP expression is switched on during monocyte-to-macrophage differentiation, is magnified by lipid loading, and is selectively lost in inflammatory macrophages, which suggests that inflammatory cells may not increase the circulating CETP pool on LXR agonist treatment.
Lakomy
Daniela
D
INSERM UMR866, Université de Bourgogne, Dijon, France.
Rébé
Cédric
C
Sberna
Anne-Laure
AL
Masson
David
D
Gautier
Thomas
T
Chevriaux
Angélique
A
Raveneau
Magalie
M
Ogier
Nicolas
N
Nguyen
Anh Thoai
AT
Gambert
Philippe
P
Grober
Jacques
J
Bonnotte
Bernard
B
Solary
Eric
E
Lagrost
Laurent
L
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010084:Oxidation-Reduction; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D011336:Probability; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
D053480:Cholesterol Ester Transfer Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein