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.

Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation

“…According to this model, the diabetic vascular wall exhibits elevated expression of both the receptor (first hit) and RAGE ligands. When a second hit—such as ischemia stress, immunological or inflammatory stimuli, physical stress, or changed lipoproteins—occurs, the body’s reaction is heightened, which leads to the development of vascular lesions rather than the restoration of vascular homeostasis [ 59 ]. In a number of clinical situations, such as diabetes [ 60 ], chronic inflammation and malignancies [ 61 ], and neurodegenerative diseases [ 62 ], RAGE is linked to enhanced host responses such as second hit.…”

Glycation of LDL: AGEs, impact on lipoprotein function, and involvement in atherosclerosis

“…Receptors of other types, for example, AGE-R1 (oligosaccharyl transferase-48), -R2 (80K-H phosphoprotein), and -R3 (galectin-3), and the class A macrophage scavenger receptor types I and II, also can recognize and bind AGE ligands. However, they were not demonstrated to transduce cellular signals after engagement by AGEs ( 12 ).…”

Ligament Alteration in Diabetes Mellitus

“…The investigation of cellular receptors for AGEs (RAGE) revealed the pathophysiological bases for the alteration of intracellular signalling as well as expression of important genes, pro-inflammatory molecules, and free-radical release [ 6 ]. The activated RAGE promotes the chain reaction of reactive oxygen species and triggers the transcription of factor NF-κB [ 4 , 13 ]. Cross-link formation in collagen fibres dictates the development of pro-inflammatory molecules, which then accelerate the creation of a disorganised cell phenotype [ 14 , 15 , 16 ].…”