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

Abstract

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-1β, 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.

Cholesterol is a significant risk factor for non-alcoholic steatohepatitis

“…As such, clinicians are cautious with prescribing statins to NASH patients, also because of potential liver damage, particularly in the case of elevated liver enzymes [30]. Experimental evidence further demonstrated that therapy aimed at blocking uptake of oxLDL was successful in preventing the development of NASH in livers of mice [31]. Similar observations were found for a therapy aimed at reducing lysosomal cholesterol in hyperlipidemic mice [32].…”

Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol

“…Serum levels of oxidized metabolites of the n-6 fatty arachidonic and linoleic acids were increased in mice fed a soybean oil-rich high-fat diet compared with mice fed a fish oil-rich high-fat diet (37). Furthermore, oxidized LDL caused Kupffer cell activation in a transgenic mouse model and thus might trigger hepatic inflammation (43). Alternatively, hepatocytes, which are damaged by oxidative stress, may activate Kupffer cells in their vicinity.…”

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

“…These macrophage-derived foam cells predominantly contain enlarged lysosomes filled with cholesterol and cholesterol crystals. Additional evidence showed that increased cholesterol storage inside lysosomes of KCs is associated with hepatic inflammation in the context of NASH [71, 72]. …”