ASP-C5L2 neutralizing antibodies alter triglyceride metabolism in vitro and in vivo (53.10)

Abstract

Abstract There are growing data that show the linkage between immune and metabolic systems. C3a is an anaphylatoxin. Its inactive product, C3a desArg, known as Acylation Stimulating Protein (ASP), is well documented as a lipogenic factor stimulating triglyceride synthesis (TGS) and glucose transport (GT). Recently, C5L2 was identified as a functional receptor of ASP. Interestingly, C5a also binds C5L2, but binding has no inflammatory response, suggesting C5L2 is a C5a decoy receptor. The aim of this study is to determine in vitro and in vivo effects of blocking ASP-C5L2 interaction using antiASP and antiC5L2 IgG. In C5L2 transfected HEK cells, antiASP or antiC5L2 competes for ASP binding (IC50: ASP 93±27 nM; antiC5L2, 199±19 nM;) and inhibit TGS and GT. In mice, antibody injection had no effect on body and tissue weight, food intake, and plasma levels of insulin, leptin, or adiponectin, but caused delayed TG (AUC: control 2.0±0.3 mM*5 h; antiASP 11.8±1.5 mM*5h p<0.001; antiC5L2 10.4±0.9 mM*5h, p<0.001) and non-esterified fatty acid (AUC: control 1.3±0.3 mM*5h; antiASP 7.2±0.5 mM*5h p<0.001; antiC5L2 6.9±0.3 mM*5h p<0.001) clearance. TG content decreased in liver (antiASP -28.0% p<0.05; anti-C5L2 −40.9% p<0.01), but increased in muscle (62.0%, antiASP, p<0.01; 81.4%, antiC5L2, p<0.001). AntiASP and antiC5L2 block ASP-C5L2 interaction, demonstrating ASP functions through C5L2 receptor. Funding: CIHR