Abstract 10244: Apolipoprotein CIII Induces Monocyte Chemoattractant Protein-1 and Interleukin-6 Expression via Toll-Like Receptor 2 Pathway in Adipocytes in vitro and in vivo
Objective: Apolipoprotein (apo) CIII, a prominent component of atherogenic dyslipidemia, independently predicts risk for coronary heart disease. We reported that apoCIII directly activates human monocytes adhesion to vascular endothelial cells. ApoCIII is elevated in patients with obesity, insulin resistance, or metabolic syndrome, and its plasma level is associated with proinflammatory adipokines. We examined the direct effect of apoCIII on adipokine expressions that are involved in these morbid conditions.
Methods and Results: Fully differentiated mouse 3T3-L1 adipocytes were incubated with apoCIII. ApoCIII activated NF-kB of 3T3-L1 adipocytes, and induced the expression of MCP-1 and IL-6. ApoCIII also activated ERK and p38. MEK1 inhibitor PD98059, but not p38 inhibitor SB203580, inhibited apoCIII-induced up-regulation of MCP-1 and IL-6. We previously reported that apoCIII activates proinflammatory signals through toll-like receptor 2 (TLR2). TLR2 blocking antibody abolished activation of NF-kB and ERK induced by apoCIII, and inhibited apoCIII-induced up-regulation of MCP-1 and IL-6. ApoCIII also reduced adiponectin expression of 3T3-L1 adipocytes, which was recovered by TLR2 blocking antibody. ApoCIII induced the expression of MCP-1 and IL-6 in TLR2-overexpressed HEK293 cells, but not wild-type HEK293 cells without TLR2. Systemic administration of apoCIII induced the expression of MCP-1 and IL-6, and decreased adiponectin expression in white adipose tissue (WAT) of wild-type mice but not of TLR2-deficient mice. ApoCIII increased plasma level of MCP-1 and IL-6, and decreased adiponectin level of wild-type mice. ApoCIII also induced the infiltration of macrophages into wild-type mice WAT.
Conclusion: Our results suggest that apoCIII activates ERK and NF-kB through TLR2, and induces proinflammatory adipokine expression and adipocyte inflammation. Thus, apoCIII and TLR2 may link dyslipidemia with inflammation and insulin resistance, contributing to atherosclerosis.
- © 2010 by American Heart Association, Inc.