Persistent Effect of Advanced Glycated Albumin Driving Inflammation and Disturbances in Cholesterol Efflux in Macrophages.

Carlos André Minanni,Marisa Passarelli,Raphael De Souza Pinto,Rodrigo Tallada Iborra,Aécio Lopes De Araújo Lira,Lígia Shimabukuro Okuda,Adriana Machado-Lima,Monique De Fátima Mello Santana,Maria Lúcia Cardillo Côrrea-Giannella,Edna Regina Nakandakare

doi:10.3390/nu13103633

Abstract

Advanced glycated albumin (AGE-albumin) impairs cholesterol efflux and contributes to inflammation in macrophages. The current study evaluated: (1) the persistence of the deleterious effect of AGE-albumin in cholesterol efflux and in inflammation, and (2) how metabolic control in diabetes mellitus (DM) contributes to attenuate the deleterious role of AGE-albumin in macrophage cholesterol homeostasis. Methods: AGE-albumin was produced in vitro or isolated from uncontrolled DM subjects’ serum before (bGC) and after improved glycemic control (aGC). Albumin samples were incubated with bone marrow-derived macrophages and 14C-cholesterol efflux or LPS- induced cytokine secretion were determined immediately, or after cell resting in culture media alone. The ABCA-1 degradation rate was determined after cell incubation with cycloheximide, and ABCA1 protein level by immunoblot. Oil Red O staining was used to assess intracellular lipid accumulation. Results: A persistent effect of AGE-albumin was observed in macrophages in terms of the secretion of inflammatory cytokines and reduced cholesterol efflux. HDL-mediated 14C-cholesterol efflux was at least two times higher in macrophages treated with aCG-albumin as compared to bGC-albumin, and intracellular lipid content was significantly reduced in aGC-albumin-treated cells. As compared to bGC-albumin, the ABCA-1 protein content in whole cell bulk was 94% higher in aCG-albumin. A 20% increased ABCA-1 decay rate was observed in macrophages treated with albumin from poorly controlled DM. AGE-albumin has a persistent deleterious effect on macrophage lipid homeostasis and inflammation. The reduction of AGEs in albumin ameliorates cholesterol efflux.

Highlights

The persistence of the effect of Advanced glycation end products (AGEs)-albumin in impairing macrophage cholesterol efflux was investigated by treating Bone Marrow-Derived Macrophages (BMDMs), previously overloaded with acetylated Low-density lipoprotein (LDL) and
Since cholesterol accumulation favors inflammation and inflammatory stress disturbs cholesterol efflux, creating a vicious cycle, we analyzed how long the effect of GAD-albumin persists in LPS-challenged macrophages
In another independent experiment dealing with different periods of time, we observed that the reduction in TNF secretion was observed only after 12 h of cell resting in the absence of GAD-albumin (Figure 2, panel C)

Summary

Introduction

Occurs by the Maillard reaction that takes place via non-enzymatic interactions between reducing sugars and the amino-terminal portion of lysine and arginine residues in proteins, phospholipids, and nucleic acids. Are much more reactive than glucose and promote rapid modification of macromolecules by AGEs, including short and middle half-life proteins. Oxoaldehydes can be generated by the oxidation of polyunsaturated fatty acids and some amino acids, as well as in inflammatory reactions mediated by myeloperoxidase. Tobacco and dietary AGEs are exogenous sources of the Maillard reaction, which occurs according to food composition, cooking time, and temperature—adding an important source of AGEs to the human body [2]

Results

Discussion

Conclusion