title: Inhibition of ABCA1 Protein Expression and Cholesterol Efflux by TNF α in MLO-Y4 Osteocytes.
abstract: Hip fracture and myocardial infarction cause significant morbidity and mortality. In vivo studies raising serum cholesterol levels as well as pro-inflammatory cytokines such as TNF α manifest bone loss and atherosclerotic vascular disease, suggesting that abnormalities of cholesterol transport may contribute to osteoporosis. We used the mouse osteocyte cell line (MLO-Y4) to investigate the effects of TNF α on the expression of cholesterol acceptor proteins such as apolipoprotein A-I (apo A-I) and apolipoprotein E (apo E), as well as on the cholesterol transporters ATP-binding cassette-1 (ABCA1), scavenger receptor class B type 1 (SRB1), and cluster of differentiation 36 (CD36). MLO-Y4 cells do not express apo A-I or apo E; however, they do express all three cholesterol transporters (ABCA1, SRB1, and CD36). Treatment of MLO-Y4 cells with TNF α had no effect on SRB1, CD36, and osteocalcin levels; however, TNF α reduced ABCA1 protein levels in a dose-dependent manner and cholesterol efflux to apo A-I. Interestingly, TNF α treatment increased ABCA1 promoter activity and ABCA1 mRNA levels, and increased liver X receptor α protein expression, but had no effect on retinoid X receptor α and retinoic acid receptor α levels. Pharmacological inhibition of p38 mitogen-activated protein (MAP) kinase, but not c-jun-N-terminal kinase 1 or mitogen-activated protein kinase (MEK), restored ABCA1 protein levels in TNF α-treated cells. These results suggest that pro-inflammatory cytokines regulate cholesterol metabolism in osteocytes in part by suppressing ABCA1 levels post-translationally in a p38 MAP kinase-dependent manner.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, L14, Jacksonville, FL, 32209, USA.
authors.forename: Kent R
authors.initials: KR
authors.lastname: Wehmeier
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, L14, Jacksonville, FL, 32209, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kurban
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, L14, Jacksonville, FL, 32209, USA.
authors.forename: Chandrikha
authors.initials: C
authors.lastname: Chandrasekharan
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, L14, Jacksonville, FL, 32209, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Onstead-Haas
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, L14, Jacksonville, FL, 32209, USA.
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, L14, Jacksonville, FL, 32209, USA. Michael.haas@jax.ufl.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D051379:Mice; D010011:Osteocytes / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018955:CD36 Antigens; D002784:Cholesterol; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; C577833:Abca1 protein, mouse; C454739:Scarb1 protein, mouse
keywords: Apolipoprotein A-I; Apolipoprotein E; Cholesterol transporters; Hip fracture; TNF α