Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases

Figure 1

Metabolic stress-mediated induction of an inflammatory response via ER stress signaling pathways. Metabolic stressors such as hypoglycemia, hyperglycemia, and elevated free fatty acids induce endoplasmic reticulum (ER) stress pathways that increase production of inflammatory cytokines. PERK activation increases IL-6, IL-23, CCL2, CCL11, and CCL20 gene expression via the JAK/STAT and eIF2α-CHOP signaling pathways. IRE1 activation results in increased secretion of a diverse group of proinflammatory cytokines through XBP1, GSK3β, and the NF-κB signaling cascade. Lastly, ER stress promotes ATF6 cleavage in the Golgi complex, which triggers proinflammatory cytokine production via the NF-κB pathway. GRP78: glucose-regulated protein 78; PERK: pancreatic ER kinase; IRE1: inositol-requiring enzyme 1; eIF2α: eukaryotic initiation factor 2 alpha; CHOP: CCAAT-enhancer-binding protein homologous protein; JAK: Janus kinase; STAT: signal transducer and activator of transcription; XBP1: X-box-binding protein 1; sXBP1: spliced X-box-binding protein 1; ATF6: activating transcription factor 6; cATF6: cleaved activating transcription factor 6; GSKβ: glycogen synthase kinase 3 beta; NF-κB: nuclear factor-kappa B; IL-6: interleukin-6; IL-23: interleukin-23; TNF-α: tumor necrosis factor alpha; IL-1β: interleukin-1 beta; CCL2: chemokine (C-C motif) ligand 2; CCL11: chemokine (C-C motif) ligand 11; CCL20: chemokine (C-C motif) ligand 20; Casp1: caspase-1.