The role of lipid-induced integrated stress response in metaflammation and atherosclerosis
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Chronic inflammation resulting from metabolic overloading of organelles (such as the endoplasmic reticulum (ER) and mitochondria that control cellular homeostasis) is a major cause of metabolic disorders including diabetes, obesity and atherosclerosis. ER is an organelle that plays a critical role in cellular metabolism through biosynthesis of lipids, protein maturation and secretion, and calcium storage. Furthermore, a stressed endoplasmic reticulum maintains cellular homeostasis by initiating a conserved stress response pathway that is known as Unfolded protein response (UPR). UPR is activated in response to diverse stimuli that disrupts ER functions and serves asva pro-survival mechanism to regain ER homeostasis. However, in prolonged or severe ER stress, chronic UPR can promote inflammation and apoptosis. Activated UPR, inflammation and necrosis are observed in and causally associated with atherosclerosis. UPR has three branches, one of which is initiated by the protein kinase RNA (PKR) like ER kinase (PERK) and signals to eukaryotic initiation factor 2a (eIF2a). This signaling arm of the UPR is also part of a larger, translational control pathway known as the integrated stress response (ISR). Activation of ISR has been observed in atherosclerosis and could promote atherosclerosis To study the contribution of ISR to atherogenesis, I took advantage of three small molecule inhibitors that can modulate this pathway. I also used a chemical-genetic approach, known as the Adenosine triphosphate (ATP) analog sensitive kinase (ASKA) technology, to interrupt PERK kinase activity. With these multiple tools, I was able to specifically interfere with ISR signaling at multiple molecular nodes in order to study the role of lipid-induced ISR in inflammation, inflammasome activation and atherosclerosis. I discovered that during lipid-induced ER stress, PERK to Activating transcription factor 4 (ATF4) signaling resulted in transcriptional induction of a mitochondrial protease, Lon protease 1 (LONP1), which degrades PTEN induced putative kinase 1 (PINK1) and blocks Parkin-mediated mitochondria clearance (or mitophagy). This in turn causes an increase in mitochondrial reactive oxygen species (ROS) production, inflammasome activation and pro-inflammatory cytokine secretion such as interleukin-1b (IL-1b) in both mouse and human macrophages. I also discovered that these inhibitors are also effective in reducing hyperlipidemia-induced inflammasome activation in Apolipoprotein E-deficient (Apoe/- ) mice and consequently, in preventing atherosclerosis progression. These results point out that intercepting with ISR signaling in hypercholestrolemia can be considered as a novel therapeutic approach that could be developed against atherosclerosis.
Integrated stress response
ATP analog sensitive kinase allele