Abstract 465: ETC-1002, a Novel Dicarboxylic Fatty Acid Analog, Inhibits Inflammatory Response in Primary Human Monocyte-Derived Macrophages as Well as in Adipose Tissue of Insulin-Resistant Mice via AMPK-Dependent Mechanisms
ETC-1002, a small molecule regulator of imbalances in lipid and carbohydrate metabolism, is an investigational drug currently in Phase 2 development to treat dyslipidemia and other cardiometabolic risk factors. In hyperlipidemic LDL receptor-deficient mice, robust antiatherosclerotic activities of ETC-1002 coincided with reduced levels of inflammatory markers in mouse atheroma. To further investigate anti-inflammatory properties of ETC-1002, human monocyte-derived macrophages (MDMs) differentiated in autologous serum were stimulated with 100 ng/ml of LPS in the absence or presence of the 10 μM and 30 μM of ETC-1002. TLR4-mediated activation of downstream kinases as well as the production of pro-inflammatory mediators were assessed with phosphokinase and protein arrays. Lower levels of JNK, cJUN, p38 and ERK phosphorylation in cells treated with ETC-1002 were consistent with reduced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-8 and MIP1α) and chemokines (CXCL10, CXCL1, CCL2 and CCL5). ETC-1002 at 30 mg/kg dose largely diminished thioglycolate-induced homing of neutrophils and macrophages into the mouse peritoneal cavity, supporting the inhibitory effect of ETC-1002 on leukocyte chemotactic and inflammatory activity. Furthermore, in a mouse model of diet-induced obesity and insulin resistance, epididymal fat pad mass and IL-6 release by inflamed adipose tissue were significantly attenuated (by 32% and 80% respectively) in animals treated with ETC-1002. Importantly, enhanced levels of AMPK phosphorylation, changes in intracellular energy charge coupled with reduced basal rates of sterol and fatty acid synthesis by human MDMs strongly supported AMPK-dependent anti-inflammatory effects of ETC-1002. Thus, our data suggest that ETC-1002, via stimulation of AMPK activity, may provide additional clinical benefits for patients with metabolic syndrome by reducing systemic inflammation and other cardiometabolic abnormalities linked to vascular disease.
- © 2012 by American Heart Association, Inc.