Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages

Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intra...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2015-08, Vol.464 (1), p.312-317
Main Authors: Manna, Pulak R., Sennoune, Souad R., Martinez-Zaguilan, Raul, Slominski, Andrzej T., Pruitt, Kevin
Format: Article
Language:English
Subjects:
ABCA1
Animals
Apolipoprotein A-I - metabolism
ATP Binding Cassette Transporter 1 - genetics
ATP Binding Cassette Transporter 1 - metabolism
Biological Transport - drug effects
Bucladesine - pharmacology
Cell Line
Cholesterol - metabolism
Cholesterol efflux
Cholesterol Esters - metabolism
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
Gene Expression Regulation
HSL
Hydrolysis - drug effects
Liver X Receptors
LXR
Macrophages
Macrophages - cytology
Macrophages - drug effects
Macrophages - metabolism
Mice
Mitochondria - drug effects
Mitochondria - metabolism
Orphan Nuclear Receptors - agonists
Orphan Nuclear Receptors - genetics
Orphan Nuclear Receptors - metabolism
Phosphoproteins - genetics
Phosphoproteins - metabolism
Receptors, Retinoic Acid - genetics
Receptors, Retinoic Acid - metabolism
Retinoids
Signal Transduction
StAR
Sterol Esterase - genetics
Sterol Esterase - metabolism
Tretinoin - analogs & derivatives
Tretinoin - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease. •Retinoids effectively enhance cholesterol efflux in mouse macrophages.•Control of StAR mediated oxysterol production is influenced by retinoids.•Retinoid mediated regulation of cholesterol efflux involves the LXR regulatory pathway.•Retinoid signaling may have implications in limiting/regressing atherosclerotic lesions.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2015.06.150