Abstract
We addressed how advanced glycation (AGE) affects the ability of apoA-IV to impair inflammation and restore the expression of genes involved in cholesterol efflux in lipopolysaccharide- (LPS-) treated macrophages. Recombinant human apoA-IV was nonenzymatically glycated by incubation with glycolaldehyde (GAD), incubated with cholesterol-loaded bone marrow-derived macrophages (BMDMs), and then stimulated with LPS prior to measurement of proinflammatory cytokines by ELISA. Genes involved in cholesterol efflux were quantified by RT-qPCR, and cholesterol efflux was measured by liquid scintillation counting. Carboxymethyllysine (CML) and pyrraline (PYR) levels, determined by Liquid Chromatography-Mass Spectrometry (LC-MS/MS), were greater in AGE-modified apoA-IV (AGE-apoA-IV) compared to unmodified-apoA-IV. AGE-apoA-IV inhibited expression of interleukin 6 (Il6), TNF-alpha (Tnf), IL-1 beta (Il1b), toll-like receptor 4 (Tlr4), tumor necrosis factor receptor-associated factor 6 (Traf6), Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/Stat3), nuclear factor kappa B (Nfkb), and AGE receptor 1 (Ddost) as well as IL-6 and TNF-alpha secretion. AGE-apoA-IV alone did not change cholesterol efflux or ABCA-1 levels but was unable to restore the LPS-induced reduction in expression of Abca1 and Abcg1. AGE-apoA-IV inhibited inflammation but lost its ability to counteract the LPS-induced changes in expression of genes involved in macrophage cholesterol efflux that may contribute to atherosclerosis.
Highlights
The inverse relationship between plasma HDL-cholesterol (HDL-C) levels and cardiovascular disease (CVD) risk is well established in epidemiological studies [1]
TNFalpha secretion was inhibited by 76 ± 10% in bone marrow-derived macrophages (BMDMs) that were preincubated with Advanced glycation end products (AGEs)-apoA-IV, this effect was less compared to unmodified-apoA-IV
The LPS-mediated increase in IL-1 beta (Il1b) was reduced by 87 ± 7:2% in BMDMs that were preincubated with unmodified-apoA-IV and by 73 ± 17:5% in BMDMs that were preincubated with AGE-apoA-IV (Figure 2(e))
Summary
The inverse relationship between plasma HDL-cholesterol (HDL-C) levels and cardiovascular disease (CVD) risk is well established in epidemiological studies [1]. Many clinical trials of agents that increase plasma HDL-C and Mendelian randomization studies have failed to demonstrate that increasing HDL-C levels reduces CV endpoints [2,3,4]. ApoA-IV mediates steps of the reverse cholesterol transport (RCT) pathway, where excess cholesterol from the arterial wall is transported to the liver for excretion into bile and feces This occurs by the interaction of lipid-free apolipoproteins and HDL to the ATP-binding cassette transporters A1 (ABCA-1) and G1 (ABCG-1), activation of lecithin cholesterol acyltransferase (LCAT), activity of cholesteryl ester transfer protein (CETP), and uptake of esterified cholesterol from HDL by the hepatic scavenger receptor B-I (SR-BI) [20,21,22,23,24,25]
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