Steatohepatitis/Metabolic Liver Disease
Article first published online: 6 JUL 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 3, pages 894–903, September 2012
How to Cite
Bieghs, V., van Gorp, P. J., Walenbergh, S. M.A., Gijbels, M. J., Verheyen, F., Buurman, W. A., Briles, D. E., Hofker, M. H., Binder, C. J. and Shiri-Sverdlov, R. (2012), Specific immunization strategies against oxidized low-density lipoprotein: A novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology, 56: 894–903. doi: 10.1002/hep.25660
Potential conflict of interest: Nothing to report.
Supported by Veni 916.76.070 (grant 2006/00496/MW), Maag Lever Darm Stichting (grants WO 08-16 and WO 09-46), and the National Institutes of Health (grant R01 AI21548).
- Issue published online: 28 AUG 2012
- Article first published online: 6 JUL 2012
- Accepted manuscript online: 15 FEB 2012 12:00AM EST
- Manuscript Received: 3 SEP 2011
- Manuscript Accepted: 6 FEB 2011
Nonalcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation combined with inflammation, which can ultimately progress into cirrhosis. Recently, we demonstrated that deletion of scavenger receptors (SRs) CD36 and SR-A in hematopoietic cells reduced hepatic inflammation. In addition to uptake of modified lipoproteins, CD36 and SR-A are also involved in other functions that can activate the inflammatory response. Therefore, the actual trigger for SR activation during NASH is unclear. Here, we hypothesized that hepatic inflammation is triggered by recognition of oxidized LDL (oxLDL) by Kupffer cells (KCs). To inhibit recognition of oxLDL by KCs, low-density lipoprotein receptor (Ldlr−/−) mice were immunized with heat-inactivated pneumococci, which were shown to induce the production of anti-oxLDL immunoglobulin M (IgM) antibodies, due to molecular mimicry with oxLDL. The mice received a high-fat, high-cholesterol diet during the last 3 weeks to induce NASH. Immunization with pneumococci increased anti-oxLDL IgM levels and led to a reduction in hepatic inflammation, as shown by reduced macrophage, neutrophil, and T cell infiltration, and reduced gene expression of tumor necrosis factor (Tnf), interleukin-6 (Il-6), interleukin-1β (Il-1b), monocyte chemoattractant protein 1 (Mcp1), and fibrosis-related genes. In immunized mice, KCs were smaller and showed fewer cholesterol crystals compared with nonimmunized mice. Conclusion: Antibodies to oxLDL play an important role in the pathogenesis of NASH. Therefore, the potential of phosphorylcholine-based vaccination strategies as a novel tool for the prevention and therapy of NASH should be tested in the future. (HEPATOLOGY 2012;56:894–903)