Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol

Abstract

Endoplasmic reticulum stress is a cellular phenomenon that has been associated with metabolic disorders, contributing to the development of obesity, fatty liver disease, and dyslipidemias. Under metabolic overload conditions, in cells with a high protein-secretory activity, such as hepatocytes and Langerhans β cells, the unfolded protein response (UPR) is critical in to maintain protein homeostasis (proteostasis). UPR integrated by a tripartite signaling system, through activating transcription factor 6, protein kinase R-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1, regulates gene transcription and translation to resolve stress and conserve proteostasis. In the current study, we demonstrated in hepatocytes under metabolic overload by saturated palmitic and stearic fatty acids, through activation of PERK signaling and CCAAT-enhancer-binding protein homologous protein (CHOP) transcription factor, an association with the expression of cyclooxygenase 2. More important, isolated exosomes from supernatants of macrophages exposed to lipopolysaccharides can also induce a metainflammation phenomenon, and when treated on hepatocytes, induced a rearrangement in cholesterol metabolism through sterol regulatory element-binding protein 2 (SREBP2), low-density lipoprotein receptor (LDLR), apolipoprotein A-I, and ABCA1. Moreover, we demonstrate the cellular effect of terpene-derived molecules, such as cryptotanshinone, isolated of plant Salvia brandegeei, regulating metainflammatory conditions through PERK pathway in both hepatocytes and β cells.Our data suggest the presence of a modulatory mechanism on specific protein translation process. This effect could be mediated by eukaryotic initiation factor-4A, evaluating salubrinal as a control molecule. Likewise, the protective mechanisms of unsaturated fatty acids, such as oleic and palmitoleic acid were confirmed. Therefore, modulation of metainflammation suggests a new target through PERK signaling in cells with a high secretory activity, and possibly the regulation of cholesterol in hepatocytes is promoted via exosomes.

Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion

“…It is likely that a competition between oleic and palmitic acid for receptors such as FFAR1 or CD36 might occur; in fact, CD36 facilitates fatty acid transport and overexpression affects insulin secretion [48]. In an important way, we previously reported that small molecules with terpene structure could regulate ER stress induced by PA, through inhibition of the eukaryotic initiation factor-4A, with an effect in CHOP and XBP1s expression [49]. Therefore, protein translation is a target that could modulate ER stress induced by lipotoxicity.…”

“…Although free fatty acid proportions in the diet are a condition associated with the development of several diseases associated with alterations in metabolism [16,38,49], it is important to consider the adipose tissue as a buffering of lipid fluxes, which could be impaired in obesity by defects in response to the dynamic metabolism that occurs after meals [52], then modifying the relationship in concentrations of saturated/unsaturated plasmatic fatty acids. Therefore, the characterization of the main effects fatty acids have upon pancreatic β-cell physiology and the UPR pathway, and the repercussion on calcium homeostasis and insulin release, allow us to broaden our understanding of the different roles of fatty acids inside β-cells, which are important metabolites to take into account in explaining the damage and treatment of novel therapeutic targets in T2DM.…”

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

“…Encouraged by previous reports from our group where docking techniques were applied with good results [47,48], in the present work, docking was employed to search possible imidazole receptors.…”

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

“…The three branches of UPR are essential in cell homeostasis to reduce ER stress and to ensure adequate synthesis of peptides such as insulin [20]. Indeed, in several reports, we have described the effect of metabolic overload on the dysregulation of UPR arms [21,22].…”

“…Given this situation, the initial events of misfolding and amyloid aggregation promote a cascade of pathological processes considered the hallmark in the progression of several chronic degenerative diseases [8][9][10][11][12][13] that might be associated with conditions related to metabolic overload [21,22]. Having this in mind, we herein characterized the role of lipid systems on the conformational transitions of the most aggregative C-terminal domain of hIAPP, and through a biomimetic approach, evaluated this condition on variants F 23 R and I 26 A that potentially could reduce aggregation.…”