AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus

Abstract

In recent decades, complex and exquisite pathways involved in the endoplasmic reticulum (ER) and inflammatory stress responses have been demonstrated to participate in the development and progression of numerous diseases, among them diabetes mellitus (DM). In those pathways, several players participate in both, reflecting a complicated interplay between ER and inflammatory stress. In DM, ER and inflammatory stress are involved in both the pathogenesis of the loss of glycemic control and the development of degenerative complications. Furthermore, hyperglycemia increases the generation of advanced glycation end products (AGEs), which in turn refeed ER and inflammatory stress, contributing to worsening glycemic homeostasis and to accelerating the development of DM complications. In this review, we present the current knowledge regarding AGEs-induced and ER/inflammation-mediated regulation of the expression of GLUT4 (solute carrier family 2, facilitated glucose transporter member 4), as a marker of glycemic homeostasis and of cardiovascular disease (CVD) development/progression, as a leading cause of morbidity and mortality in DM.

Keywords: GLUT4; advanced glycation end product; atherogenesis; cardiovascular disease; diabetes mellitus; endoplasmic reticulum stress; hyperglycemia.

Figure 1

Advanced glycation end products (AGE)-induced regulation of glycemic homeostasis and glycemic homeostasis: participation of inflammatory and endoplasmic reticulum stress. In adipose and muscle tissues, AGE/CML binding to AGER and TLR activate the ER-stress response, including increased expression and/or activation of BIP, ENPL, XBP1, DDIT3, IRE1 and TRAF2. XBP1 and BIP activate ATF6, which is a repressor of the transcription factor PRGC1A and MEF2A (enhancers of Slc2a4 gene), thus decreasing Slc2a4 expression. On the other, IRE1/TRAF2 activation overlap the inflammatory pathway phosphorylating IKKA/B, and promoting NFKB dissociation and migration into the nucleus, where it plays a potent repressor effect upon Slc2a4 gene expression. Besides, intracellular MGO can contribute to the increase in the activity of proinflammatory cytokines, reinforcing this pathway. These effects on the Slc2a4 gene expression decreases GLUT4 synthesis and plasma membrane content, eventually decreasing insulin-induced glucose uptake, and establishing IR. In turn, IR leads to hyperglycemia, which can cause T2D or worsen preexisting DM. Symbols are: AGE, advanced glycated end product; AGER, advanced glycation end product-specific receptor, alias RAGE; ATF6, cyclic AMP-dependent transcription factor ATF; BIP, endoplasmic reticulum chaperone BIP, alias GRP78; CEBPA, CCAAT enhancer binding protein alpha; CML, carboxymethyl-lysine; DM, diabetes mellitus; DDIT3, DNA damage-inducible transcript 3 protein, alias CHOP10/GADD153; DM, diabetes mellitus; ENPL, endoplasmin, alias GRP94; ER, endoplasmic reticulum; GLUT4, solute carrier family 2, facilitated glucose transporter member 4; IKKA/B, inhibitor of nuclear factor kappa-B kinase subunits alpha/beta; IR, insulin resistance; IRE1, inositol requiring enzyme-1; MGO, methylglyoxal; MEF2A, myocyte enhancer factor 2A; NFKB, nuclear factor NF-kappa-B; PRGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, alias PGC1A; Slc2a4, solute carrier family 2 member 4 gene; T2D, type 2 diabetes mellitus; TLR, toll-like receptors; TRAF2, TNF receptor-associated factor 2; XBP1, X-box-binding protein 1. Names and symbols of proteins are in accordance with the UNIPROT database (https://www.uniprot.org/, accessed on 2 November 2021). Parts of the figure were drawn from Servier Medical Art (https://smart.servier.com/, accessed on 2 November 2021).

Figure 2

Advanced glycation end products-induced atherogenesis and CVD development: participation of inflammatory and endoplasmic reticulum stress. Glycated LDL reaches the arterial intima inducing circulating monocyte chemotaxis. Differentiated macrophages take up modified LDL by the scavenger receptors which induces intracellular cholesterol accumulation. In addition, advanced glycated albumin (AGE-albumin), modified in blood circulation or in the arterial intima is taken up by AGER. This induces the generation of ROS by NOX4 and mitochondrial respiratory chain activation. Moreover, AGEs induce inflammation and ER stress, with increased expression of BIP, ENPL, ATF6, EIF2AK3 and DDIT3 that relates to ABCA1 degradation by the ubiquitin-proteasomal and lysosomal systems. Ultimately, a dramatic decrease in ABCA1 protein content in macrophage foam cells is observed, leading to the reduction in the APOA1 and pre-beta HDL-mediated cholesterol efflux. Although AGEs do not alter ABCA1 mRNA, they reduce the gene expression of ABCG1, by an LXR-dependent mechanism, then compromising the HDL-mediated cholesterol efflux. The accumulation of cholesterol and oxysterols perpetuates the generation of ROS, inflammatory cytokines and AGEs, which culminates in a necrotic core formation, with apoptosis, pyroptosis, plaque instability and rupture. The deleterious effects of AGEs on macrophage homeostasis damage the cholesterol flux to the liver by the reverse cholesterol transport contributing to the independent relation of AGEs with CVD. Symbols are: ABCA1, phospholipid-transporting ATPase ABCA1; ABCG1, ATP binding cassette transporter G-1 AGE, advanced end product; AGER, advanced glycation end product-specific receptor, alias RAGE; APOA1, apolipoprotein A-1; ATF6, cyclic AMP-dependent transcription factor ATF-6; BIP, endoplasmic reticulum chaperone BIP, alias GRP78; CVD, cardiovascular disease; DDIT3, DNA damage-inducible transcript 3 protein, alias CHOP10/GADD153; EIF2AK3, eukaryotic translation initiation factor 2-alpha kinase 3, alias PERK; ENPL, endoplasmin, alias GRP94; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LXR, liver X receptor; NOX4, NADPH oxidase 4; ROS, reactive oxygen species. Names and symbols of proteins are in accordance with the UNIPROT database (https://www.uniprot.org/, accessed on 2 November 2021). Parts of the figure were drawn from Servier Medical Art (https://smart.servier.com/, accessed on 2 November 2021).