Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) - Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

Abstract

Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.

Keywords: RAGE axis; cardiometabolic disease; glycation; lipid metabolism; lipoxidation; non-alcoholic fatty liver disease; obesity.

Figure 1

Proposed model of RAGE/DIAPH1 in glycation and lipid metabolism and implications for cardiometabolic disease. Diets high in fats and sugars trigger the production of AGEs and ALEs, which are ligands of RAGE. In very early events in atherogenesis, the production of foam cells in monocytes/macrophages and smooth muscle cells may be facilitated by AGE/ALE signaling through RAGE/DIAPH1. Foam cells, characterized by heightened inflammation in the atherosclerotic vessel wall, produce RAGE ligand DAMPs, which perpetuate inflammatory responses via RAGE/DIAPH1; one consequence of which is upregulation of IRF7, which itself perturbs inflammation and cholesterol metabolism pathways and processes that exacerbate progression of atherosclerosis and delay its regression. AGEs and ALEs also accumulate in obese adipose tissue and liver, the latter especially relevant to the pathogenesis of NAFLD. Obesity and NAFLD contribute to the development of insulin resistance, and, therefore, the potential for development of hyperglycemia and processes that amplify AGE/ALE production and their vicious cycle of cellular stress. The optimal means to divert RAGE-DIAPH1 binding and downstream signaling is under intensive investigation and is hypothesized to reduce cardiometabolic risk and its consequences.