Abstract
Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at -46 to -40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.
Highlights
Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle
While earlier studies suggested that Lp(a) serum levels are mostly determined by genetic factors [7, 8], several recent reports indicate that Lp(a) is induced by mediators of the innate immune system [9,10,11]
In a recent clinical study from Schultz et al [14], we have shown that interleukin 6 (IL-6) inhibition due to the monoclonal antibody TCZ results in a reduction of Lp(a) serum levels to a greater extent than the drug niacin, which for a long period of time has been suggested to be the standard therapy for that metabolic abnormality [18]
Summary
Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is caused by chronic inflammation. We found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans. Studies have demonstrated apo(a) to be genetically polymorphic [2] with apo(a) isoproteins ranging in approximate size from 200 to 800 kDa [5] These different apo(a) phenotypes are thought to importantly determine the rates of hepatic synthesis of apo(a) and Lp(a) serum concentrations with an inverse correlation between the two parameters [6,7,8]. While earlier studies suggested that Lp(a) serum levels are mostly determined by genetic factors [7, 8], several recent reports indicate that Lp(a) is induced by mediators of the innate immune system [9,10,11].
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