Specific immunization strategies against oxidized low-density lipoprotein: A novel way to reduce nonalcoholic steatohepatitis in mice.

BACKGROUND: Non-alcoholic 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 (SR) CD36 and SR-A in haematopoietic 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). METHODS: To inhibit recognition of oxLDL by KCs, Ldlr(-/-) mice were immunized with heat-inactivated pneumococci, which were shown to induce the production of anti-oxLDL IgM antibodies, due to molecular mimicry with oxLDL. The mice received a high fat cholesterol (HFC) diet during the last 3 weeks to induce NASH. RESULTS: 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 Tnf, Il-6, Il-1beta, Mcp1 and fibrosis related genes. In immunized mice, KCs were smaller and showed less cholesterol crystals compared to non-immunized mice. CONCLUSION: Antibodies to oxLDL play an important role in the pathogenesis of NASH. Therefore, the potential of PC-based vaccination strategies as a novel tool for the prevention and therapy of NASH should be tested in future. (HEPATOLOGY 2012.)