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Journal of Lipid Research, Vol. 48, 794-805, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

ApoE^–/–Fas^–/– C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia

Xuebing Feng^1,*, Hongyun Li^*, Alexis A. Rumbin^*, Xuping Wang, Antonio La Cava^*, Katherine Brechtelsbauer^*, Lawrence W. Castellani, Joseph L. Witztum, Aldons J. Lusis and Betty P. Tsao^2,*

^* Division of Rheumatology, Department of Medicine, University of California, Los Angeles, CA
Departments of Microbiology, Immunology, and Molecular Genetics, Medicine, and Human Genetics and the Molecular Biology Institute, University of California, Los Angeles, CA
Department of Medicine, University of California San Diego, La Jolla, CA

Published, JLR Papers in Press, January 26, 2007.

¹ Present address of X. Feng: Department of Rheumatology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.

²To whom correspondence should be addressed. e-mail: btsao{at}mednet.ucla.edu

To establish a mouse model of accelerated atherosclerosis in lupus, we generated apolipoprotein E-deficient (apoE^–/–) and Fas^lpr/lpr (Fas^–/–) C57BL/6 mice. On a normal chow diet, 5 month old apoE^–/–Fas^–/– mice had enlarged glomerular tuft areas, severe proteinuria, increased circulating autoantibody levels, and increased apoptotic cells in renal and vascular lesions compared with either single knockout mice. Also, double knockout mice developed increased atherosclerotic lesions but decreased serum levels of total and non-HDL cholesterol compared with apoE^–/–Fas^+/+ littermates. Moreover, female apoE^–/–Fas^–/– mice had lower vertebral bone mineral density (BMD) and bone volume density (BV/TV) than age-matched female apoE^–/–Fas^+/+ mice. Compared with apoE^–/–Fas^+/+ and apoE^+/+Fas^–/– mice, apoE^–/–Fas^–/– mice had decreased circulating oxidized phospholipid (OxPL) content on apoB-100 containing lipoprotein particles and increased serum IgG antibodies to OxPL, which were significantly correlated with aortic lesion areas (r = 0.58), glomerular tuft areas (r = 0.87), BMD (r = –0.57), and BV/TV (r = –0.72). These results suggest that the apoE^–/–Fas^–/– mouse model might be used to study atherosclerosis and osteopenia in lupus. Correlations of IgG anti-OxPL with lupus-like disease, atherosclerosis, and bone loss suggested a shared pathway of these disease processes.

Supplementary key words oxidized phospholipid • apoptosis • autoantibodies

Abbreviations: apoE, apolipoprotein E; B6, C57BL/6; BMD, bone mineral density; BV/TV, bone volume density; dsDNA, double-stranded DNA; OxLDL, oxidized low-density lipoprotein; OxPL, oxidized phospholipid; PGPC, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine; POVPC, 1-palmitoyl-2(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; RLU, relative light units; SLE, systemic lupus erythematosus; TUNEL, TdT-mediated dUTP-biotin nick end labeling

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