Liver X receptor activation controls intracellular cholesterol trafficking and esterification in human macrophages.
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.
Rigamonti
E
E
UR 545 Inserm, Institut Pasteur de Lille and Université de Lille 2, France.
Helin
L
L
Lestavel
S
S
Mutka
A L
AL
Lepore
M
M
Fontaine
C
C
Bouhlel
M A
MA
Bultel
S
S
Fruchart
J C
JC
Ikonen
E
E
Clavey
V
V
Staels
B
B
Chinetti-Gbaguidi
G
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000032:analysis / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005487:Foam Cells / Q000378:metabolism; D006023:Glycoproteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000077296:Niemann-Pick C1 Protein; D057093:Orphan Nuclear Receptors; D011374:Progesterone / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D033921:Vesicular Transport Proteins
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D002788:Cholesterol Esters; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D033921:Vesicular Transport Proteins; D011374:Progesterone; D002784:Cholesterol