title: Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages.
abstract: 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.
authors.affiliation: Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. Electronic address: pulak.manna@ttuhsc.edu.
authors.forename: Pulak R
authors.initials: PR
authors.lastname: Manna
authors.affiliation: Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Souad R
authors.initials: SR
authors.lastname: Sennoune
authors.affiliation: Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Martinez-Zaguilan
authors.affiliation: Department of Dermatology, University of Alabama Birmingham, VA Medical Center, AL 35294, USA.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
authors.affiliation: Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pruitt
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006868:Hydrolysis / Q000187:drug effects; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D003994:Bucladesine; D002784:Cholesterol; D002788:Cholesterol Esters; D017868:Cyclic AMP-Dependent Protein Kinases; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D002787:Sterol Esterase; D014212:Tretinoin; D000098682:Steroidogenic Acute Regulatory Protein; C577833:Abca1 protein, mouse; C105492:9,13-retinoic acid
keywords: ABCA1; Cholesterol efflux; HSL; LXR; Macrophages; Retinoids; StAR