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Inhibition of ABCA1 Protein Expression and Cholesterol Efflux by TNF α in MLO-Y4 Osteocytes

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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.

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Acknowledgments

This work was funded by a Grant from the University of Florida—Jacksonville College of Medicine to Dr. Kent Wehmeier.

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Authors and Affiliations

  1. 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

    Kent R. Wehmeier, William Kurban, Chandrikha Chandrasekharan, Luisa Onstead-Haas, Arshag D. Mooradian & Michael J. Haas

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  1. Kent R. Wehmeier
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Correspondence to Michael J. Haas.

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Kent R. Wehmeier, William Kurban, Chandrikha Chandrasekharan, Luisa Onstead-Haas, Arshag D. Mooradian, and Michael J. Haas declare that they have no conflict of interest.

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Wehmeier, K.R., Kurban, W., Chandrasekharan, C. et al. Inhibition of ABCA1 Protein Expression and Cholesterol Efflux by TNF α in MLO-Y4 Osteocytes. Calcif Tissue Int 98, 586–595 (2016). https://doi.org/10.1007/s00223-015-0106-2

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  • DOI: https://doi.org/10.1007/s00223-015-0106-2

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