Abstract
Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use.
Highlights
HDL continues to attract interest because its levels are inversely associated with the risk of cardiovascular disease [1]
These results show that injection of Fc-CETP6 induces production of antibodies against cholesteryl ester transfer protein (CETP), which reduce CETP activity
We designed and produced a novel Fc-CETP6 vaccine. This vaccine induced the generation of anti-CETP antibodies that reduced plasma CETP activity, alleviating the development of both atherosclerosis and non-alcoholic steatohepatitis (NASH) in high fat/cholesterol (HFC) diet-fed rabbits
Summary
HDL continues to attract interest because its levels are inversely associated with the risk of cardiovascular disease [1]. This may be attributed to its having various potentially anti-atherogenic properties, such as reverse cholesterol transport, antiinflammatory, anti-oxidative, and anti-thrombotic effects [2]. Recent studies have suggested that the pathogenesis of NASH involves scavenger receptor-mediated uptake of ox-LDL by macrophages in the liver [6], [7]. This may explain, at least in part, why NASH is an important risk factor for cardiovascular disease [8]. It is not known if increasing HDL levels by CETP inhibition can ameliorate NASH
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