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Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

Gene Therapy volume 18, pages 835–841 (2011)Cite this article

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Abstract

Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR−/−) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRα (Lenti-SP-LXRα) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRα mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRα gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR−/− mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.

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Acknowledgements

We are grateful to Ronald M Evans (The Salk Institute for Biological Studies, San Diego, CA, USA) for providing mouse LXRα cDNA (pCMX-mLXRα) and Jessica Han for her technical assistance. This study was supported by a research grant from the Research Division of the Department of Veterans Affairs and a Grant-in-Aid from the Texas Affiliate of the American Heart Association.

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Authors and Affiliations

  1. Department of Medicine, Audie L Murphy Division, University of Texas Health Science Center, and the South Texas Veterans Health Care System, San Antonio, TX, USA

    G Li, K C Biju, X Xu, Q Zhou, C Chen, A J Valente, W He, G L Freeman, S S Ahuja, R A Clark & S Li

  2. Department of Pathology, Audie L Murphy Division, University of Texas Health Science Center, and the South TexasVeterans Health Care System, San Antonio, TX, USA

    R L Reddick

  3. Department of Pharmacology, Audie L Murphy Division, University of Texas Health Science Center, and the South Texas Veterans Health Care System, San Antonio, TX, USA

    S Li

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  1. G Li
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Correspondence to S Li.

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Li, G., Biju, K., Xu, X. et al. Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice. Gene Ther 18, 835–841 (2011). https://doi.org/10.1038/gt.2011.29

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  • DOI: https://doi.org/10.1038/gt.2011.29

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