75-OR: IL-6R (Trans Signaling) Is a Major Modulator of Reverse Cholesterol Transport in Lipid-Laden Macrophages

The onset of obesity is vastly associated with low levels of high-density lipoprotein cholesterol (HDL-C) , which predisposes to cardiovascular diseases. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially in lipid metabolic homeostasis. Yet, the precise nature of the HDL/IL-6 dynamics has not been fully elucidated. Therefore, we evaluated the expression of IL-6 in circulatory monocytes of the individuals with various body mass index and we also determined their lipid profile. Our data show that monocytic IL-6 expression was found to be negatively associated with HDL-C levels in obese individuals and positively associated with C-reactive protein and other monocytic pro-inflammatory markers. Mechanistically, chemical inhibition or genetic silencing of IL-6 receptor gp130/IL-6ST gene induced severe upregulation of intracellular lipid accumulation in THP-1 transformed macrophages that was found to be further augmented under fatty acid rich culture conditions. Moreover, analysis of the genes involved in lipid and cholesterol metabolism showed up-regulation of the LDLR along with a remarkable inhibition of ATP Binding Cassette (ABC) Subfamily transporters ABCG1 and ABCB1. We also found that the macrophages lacking gp130/IL-6 receptors had very low beta-oxidation genes expression (CPT1A and CPT2) , however, with no effect on triglyceride synthesis genes expression (DGAT, ACACA, FASN and Srebp1c) .

In conclusion, our data support a role for IL-6 receptor signaling pathways in lipid alteration and cholesterol efflux which may have potential as a therapeutic target for metabolic syndrome.