title: The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages.
abstract: The critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial wall of arteries, and their transformation from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). To define genes that are specifically expressed during the transformation of macrophages into foam cells, we have performed a subtractive library screening utilizing mRNA isolated from THP-1 macrophages and foam cells. From this analysis, we have identified adipocyte lipid binding protein (ALBP/aP2) as a gene that is highly upregulated in foam cells in response to oxLDL. Furthermore, overexpression the ALBP gene using an adenovirus construct enhanced the accumulation of cholesterol ester in macrophage foam cells, probably due to an increase in transcription since oxLDL enhanced ALBP promoter activity in experiments using a promoter-luciferase reporter gene construct. The induction of ALBP by oxLDL probably involved activation of peroxisome proliferator-activated receptor gamma (PPARgamma) transcription factors, since four different endogenous PPARgamma ligands, including 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE), two oxidized lipid components of oxLDL, as well as 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and retinoic acid (RA), all induced ALBP expression in macrophage/foam cells. Finally, ALBP was found to be highly expressed in vivo in macrophage/foam cells of human atherosclerotic plaques. These observations suggest that oxLDL-mediated increase in ALBP gene expression accelerate cholesterol ester accumulation, and that this is an important component of the genetic program regulating conversion of macrophages to foam cells. The observation that ALBP is readily detected in foam cells in active atherosclerotic lesions implicates a role for ALBP in human vascular disease. The induction of ALPB expression by oxLDL likely involves activation of PPARgamma by components of oxLDL (9-HODE and 13-HODE) that also function as PPARgamma ligands. Our results add to the concern that the clinical use of insulin-sensitizing PPARgamma agonists (i.e. thiazolidinediones) to treat Type 2 Diabetes could exacerbate atherosclerosis, and highlight the need for clinical trials that address this issue.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, STB/514, 114 Doughty Street, Charleston, SC 29403, USA. fuy@musc.edu
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.forename: Nanlan
authors.initials: N
authors.lastname: Luo
authors.forename: Maria F
authors.initials: MF
authors.lastname: Lopes-Virella
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
mesh_terms: D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005487:Foam Cells / Q000378:metabolism*; D015723:Gene Library; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins
chemical_list: D002352:Carrier Proteins; C493410:FABP4 protein, human; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D008077:Lipoproteins, LDL; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C099252:oxidized low density lipoprotein