Abstract 11182: Novel Tlr7 and Tlr9 Dual Antagonist Lowers Cholesterol in Hyperlipidemic Mice Through Il-10-Mediated Activation of Lxr and Increased Fecal Neutral Sterol Loss
Hyperlipidemia is characterized by abnormal or elevated lipids and/or lipoproteins levels in the blood. Elevated lipids levels have been observed in autoimmune diseases, such as lupus, rheumatoid arthritis and psoriasis, leading to a significant increase in cardiovascular disease-related morbidity and mortality. There is growing evidence that certain Toll like receptors (TLR) are involved in inflammation processes that contribute to alteration of lipid levels. Our studies have shown that treatment with a dual antagonist of TLR7 and TLR9 (antagonist) lowers total cholesterol (TC), LDL-cholesterol (LDL-c), Triglycerides and Leptin in a dose dependent manner in C57BL/6 and ApoE−/− mice fed with high fat diet (HFD). Lowering of serum levels of TC was inversely correlated with levels of IL−10. Antagonist treatment was associated with inhibition of plaque formation and improvement of liver and kidney steatosis. Further studies have demonstrated lowering of TC with concomitant induction of IL-10 expression in a treatment model of HFD-induced hyperlipidemia. Antagonist treatment of mice fed with HFD for 16 weeks showed reduced serum levels of TC without an impact on body weight. Additionally, qualitative and quantitative changes in fecal content of fatty acids and neutral sterols were observed in treated mice cohort. To study the effect of antagonist on hyperlipidemia, an analysis of gene expression profiles induced in the liver of mice fed an HFD and treated with the antagonist was carried out. Expression levels of selected genes in liver and large intestine were studied by quantitative PCR. Results obtained demonstrated that treatment with antagonist results in increased levels of IL-10, Liver X receptor (LXR) and ABC transporter G1 (ABCG1) gene expression in hepatic cells. Liver expression of ABCA1 gene was unaffected. However, the expression of both ABCG5 and ABCG8 genes was significantly elevated in the large intestine of mice treated with antagonist. These results suggest that the TLR7 and 9 dual antagonist achieves lowering of TC and other cardiovascular risk factors through the enhanced fecal cholesterol excretion via induction of anti inflammatory cytokines and IL-10-mediated activation of LXR, ABCG1, ABCG5 and ABCG8.
- © 2010 by American Heart Association, Inc.