Abstract 16496: Electronegative Low-Density Lipoprotein of Metabolic Syndrome Patients Induces Release of Inflammatory Adipocytokines and Accumulation of M1 Macrophages in Adipose Tissue
Background: Inflammation-associated dysfunction of adipocytes plays an etiologic role in insulin resistance and diabetes development. To delineate the mechanism, we examined the in vivo and in vitro effects LDL of metabolic syndrome (MetS) patients on adipose tissue.
Methods and Results: Plasma LDL was isolated from MetS patients and healthy control subjects with similar LDL cholesterol levels (142.2±41.8 vs. 140.9±44.5 mg/dL; n=29 each). Anion-exchange chromatography showed that MetS LDL contained a higher percentage of the most electronegative subfraction, L5, than control LDL (5.3±4.9% vs. 2.1±1.4%; P<0.001). Tail-vein injections of human L5 but not the least electronegative L1 (n=5 each, 3 mg/kg/day x 4 weeks) into wild type C57BL/6 mice induced accumulation of F4/80+/CD11c+ M1 macrophages, with adjacent apoptotic adipocytes, in the adipose tissue (Figure, Panel A). L5 signals through lectin-like oxidized LDL receptor-1 (LOX-1). Treating human adipocytes with L5 but not L1 induced release of inflammatory adipocytokines (IL-6, IL-8, CXCL10, RANTES) and complement (C5/C5a) into the culture-conditioned medium (CCM); neutralizing LOX-1 attenuated the release (Figure, Panel B). Incubating human THP-1 monocytes with L5-CCM resulted in a 300 fold enhancement of transwell migration in 24 hours, when compared with incubating the cells with L1-CCM (n=6; P<0.001). Migrated cells exhibited positive macrophage marker PM-2K, indicating transformation of monocytes into macrophages induced by the L5-CCM.
Conclusions: L5 induces macrophage transformation from monocytes via releasing inflammatory cytokines from adipocytes; aggregation of M1 macrophages in the adipose tissue further worsens adipocytic dysfunction. Thus, increased LDL electronegativity may be a predisposing factor for diabetes in MetS.
Author Disclosures: C. Chu: None. H. Chan: None. L. Ke: None. H. Chan: None. C. Wang: None. K. Cheng: None. J. Lu: None. H. Lee: None. H. Kuo: None. C. Chang: None. S. Sheu: None. T. Sawamura: None. W. Lai: None. C. Chen: None.
- © 2014 by American Heart Association, Inc.