Lipid Chaperones and Metabolic Inflammation
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Abstract:
Over the past decade, a large body of evidence has emerged demonstrating an integration of metabolic and immune response pathways. It is now clear that obesity and associated disorders such as insulin resistance and type 2 diabetes are associated with a metabolically driven, low-grade, chronic inflammatory state, referred to as “metaflammation.” Several inflammatory cytokines as well as lipids and metabolic stress pathways can activate metaflammation, which targets metabolically critical organs and tissues including adipocytes and macrophages to adversely affect systemic homeostasis. On the other hand, inside the cell, fatty acid-binding proteins (FABPs), a family of lipid chaperones, as well as endoplasmic reticulum (ER) stress, and reactive oxygen species derived from mitochondria play significant roles in promotion of metabolically triggered inflammation. Here, we discuss the molecular and cellular basis of the roles of FABPs, especially FABP4 and FABP5, in metaflammation and related diseases including obesity, diabetes, and atherosclerosis.Keywords:
Homeostasis
The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.
Chemical chaperone
Chaperone (clinical)
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The endoplasmic reticulum (ER) is the site of synthesis and maturation of proteins designed for secretion or for localization on the cell membrane. Various types of stress from both inside and outside cells disturb ER function, thus causing unfolded or misfolded proteins to accumulate in the ER. To improve and maintain the ER functions against such stresses, the ER stress response pathway is activated. However, when the stress is prolonged or severe, apoptosis pathways are activated to remove damaged cells. It was recently reported that the ER stress pathway is also involved in the inflammatory response, whereby inflammation induces ER stress, and ER stress induces an inflammatory response. Therefore, the ER stress response pathway is involved in various diseases, including cardiovascular diseases such as atherosclerosis and ischemic diseases, in various ways. The ER stress pathway may represent a novel target for the treatment of these diseases.
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Secretory protein
Endoplasmic-reticulum-associated protein degradation
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OBJECTIVE: To summarize the advances of domestic and foreign research on reticulum stress and unfolded protein response,to review its molecular mechanism and the pathways of the cell survival and apoptosis associated with reticulum stress.METHODS:The full text database of PubMed and CNKI were searched,and the words endoplasmic reticulum stress/unfolded protein response/apoptosis were used as Key words:.To retrieve the literature about reticulum stress and unfolded protein response from Jan.1990 to Jan.2010,and then 24 were used in analysis at last.RESULTS:The reticulum(ER),an important intracellular organelle of eukary-ocyte,is the factory for folding and maturation of newly synthesized transmembrane and secretory proteins.Accumulation of unfolded or misfolded proteins in ER leads to ER stress and triggers the unfolded protein response(UPR).UPR is a highly conserved self-protective mechanism by ameliorating the accumulation of unfolded or misfolded proteins in the ER;however if ER stress is severe or protracted,cell apoptosis may be induced.CONCLUSION:Though the molecular mechanism of reticulum stress and unfolded protein response is clear,there are still present some questions,and so it needs further study.
Endoplasmic-reticulum-associated protein degradation
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Endoplasmic-reticulum-associated protein degradation
Homeostasis
Chaperone (clinical)
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Different abiotic and biotic stresses lead to the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress. In response to ER stress, cells activate various cytoprotective responses, enhancing chaperon synthesis, protein folding capacity, and degradation of misfolded proteins. These responses of plants are called the unfolded protein response (UPR). ER stress signaling and UPR can be regulated by salicylic acid (SA), but the mode of its action is not known in full detail. In this review, the current knowledge on the multifaceted role of SA in ER stress and UPR is summarized in model plants and crops to gain a better understanding of SA-regulated processes at the physiological, biochemical, and molecular levels.
Tunicamycin
Folding (DSP implementation)
Endoplasmic-reticulum-associated protein degradation
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The endoplasmic reticulum (ER) is a multifunctional organelle which co-ordinates protein folding, lipid biosynthesis, calcium storage and release. Perturbations that disrupt ER homeostasis lead to ER stress and upregulation of a signaling pathway called the unfolded protein response (UPR). The UPR while robust in young animals appears to be compromised with aging; many of the components of the UPR have decreased expression and activity with age. There is also considerable evidence of oxidative damage. There are suggestions that an impaired UPR may contribute to the acceleration of neurodegenerative disorders.
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Homeostasis
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Homeostasis
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Unfolded protein response (UPR) is an adaptive response, allowing the endoplasmic reticulum (ER) responds to an accumulation of unfolded proteins in its lumen, also known as ER stress. The ER reacts to ER stress through ER transmembrane protein sensors, thus activating intracellular signal transduction pathways. The UPR is interconnected with inflammation through reactive oxygen species production, activation of nuclear factor-kB (NF-kB) and JUN N-terminal kinase (JNK) via inositol-requiring enzyme 1 (IRE1) and induction of acute-phase response. LCN2 is one of the acute phase proteins that are induced under inflammatory conditions and up-regulated during ER stress. We therefore examined the ER stress responses in LCN2-/- condition.
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