scholarly journals ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-shan Wan ◽  
Xiang-hong Lu ◽  
Ye-cheng Xiao ◽  
Yuan Lin ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Glucose And Lipid Metabolism ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

scholarly journals Activation of Hepatitis B Virus S Promoter by a Cell Type-Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress

2005 ◽  
Vol 25 (17) ◽  
pp. 7522-7533 ◽  
Author(s):  
Zhi-Ming Huang ◽  
Thomas Tan ◽  
Hiderou Yoshida ◽  
Kazutoshi Mori ◽  
Yanjun Ma ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Active Form ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Cell Type ◽  
B Virus

ABSTRACT IRE1-alpha is an integral membrane protein of the endoplasmic reticulum (ER) that is a key sensor in the cellular transcriptional response to stress in the ER. Upon induction of ER stress, IRE1-alpha is activated, resulting in the synthesis of the active form of the transcription factor XBP1 via IRE1-mediated splicing of its mRNA. In this report, we have examined the role of IRE1-alpha and XBP1 in activation of the hepatitis B virus S promoter by ER stress. Cotransfection experiments revealed that overexpression of either IRE1-alpha or XBP1 activated this promoter. Conversely, cotransfected dominant-negative IRE1-alpha or small interfering RNA directed against XBP1 decreased the activation of the S promoter by ER stress, confirming an important role for the IRE1-alpha/XBP1 signaling pathway in activation of the S promoter. However, XBP1 does not bind directly to the S promoter; rather, a novel S promoter-binding complex that does not contain XBP1 is induced in cells undergoing ER stress in an XBP1-dependent manner. This complex, as well as transcriptional activation of the S promoter, is induced by ER stress in hepatocytes but not in fibroblasts, despite the presence of active XBP1 in the latter. Thus, the hepatitis B virus S promoter responds to a novel, cell type-restricted transcriptional pathway downstream of IRE1-alpha and XBP1.

scholarly journals Endoplasmic Reticulum Stress Induces the Expression of Fetuin-A to Develop Insulin Resistance

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 2974-2984 ◽  
Author(s):  
Horng-Yih Ou ◽  
Hung-Tsung Wu ◽  
Hao-Chang Hung ◽  
Yi-Ching Yang ◽  
Jin-Shang Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
High Glucose ◽  
Normal Glucose Tolerance ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Fetuin A ◽  
Nonalcoholic Fatty Liver ◽  
Diagnosed Diabetes

Fetuin-A is a biomarker reported to be important in many metabolic disorders, including obesity, diabetes, and hepatic steatosis. Although it is well known that fetuin-A is increased in diabetes and nonalcoholic fatty liver disease (NAFLD), the levels of fetuin-A in diabetic patients with NAFLD are unknown. Furthermore, the regulation of fetuin-A expression is still obscure. In this study, a total of 180 age- and sex-matched subjects with normal glucose tolerance, NAFLD, newly diagnosed diabetes (NDD), and NDD with NAFLD were recruited. We found that the levels of fetuin-A were significantly increased in NDD with NAFLD as compared with NDD or NAFLD subjects. We further used HepG2 cells to investigate the regulation of fetuin-A. Treatment with endoplasmic reticulum (ER) stress activator, thapsigargin, increased the expression of fetuin-A mRNA and protein in a time- and dose-dependent manner. Pretreatment with ER stress inhibitor, 4-phenylbutyrate, reversed high glucose or palmitate-induced fetuin-A expression. Moreover, treatment with 4-phenylbutyrate in both streptozotocin-induced and high-fat diet-induced diabetic mice not only decreased hepatic fetuin-A levels but also improved hyperglycemia. Taken together, we found that fetuin-A levels were increased in diabetes patients with NAFLD. Moreover, ER stress induced by high glucose and palmitate increased the expression of fetuin-A and further contributed to the development of insulin resistance.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals Lipid perturbation-activated IRE-1 modulates autophagy and lipolysis during endoplasmic reticulum stress

2018 ◽  
Author(s):  
Jhee Hong Koh ◽  
Lei Wang ◽  
Caroline Beaudoin-Chabot ◽  
Guillaume Thibault
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Lipid Droplet ◽  
Metabolic Diseases ◽  
Phospholipid Composition ◽  
Emerging Diseases ◽  
Lipid Homeostasis ◽  
Dependent Manner ◽  
Proteotoxic Stress

ABSTRACTMetabolic disorders such as obesity and nonalcoholic fatty liver disease (NAFLD) are emerging diseases that affect the global population. One facet of these disorders is attributed to the disturbance of membrane lipid composition. Perturbation of endoplasmic reticulum (ER) homeostasis through changes in membrane phospholipid composition results in activation of the unfolded protein response (UPR) and causes dramatic translational and transcriptional changes in the cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1, and PERK mediate cellular processes upon ER stress. The role of the UPR in proteotoxic stress caused by the accumulation of misfolded proteins is well understood but much less so under lipid perturbation-induced UPR (UPRLP). We found that genetically disrupted phosphatidylcholine synthesis in C. elegans causes, lipid perturbation, lipid droplet accumulation, and induced ER stress, all hallmarks of NAFLD. Transcriptional profiling of UPRLP animals shows a unique subset of genes modulated in an UPR-dependent manner that is unaffected by proteotoxic stress (UPRPT). Among these, we identified autophagy genes bec-1 and lgg-1 and the lipid droplet-associated lipase atgl-1 to be modulated by IRE-1. Considering the important role of lipid homeostasis and how its impairment contributes to the pathology of metabolic diseases, our data uncovers the indispensable role of a fully functional UPR program in regulating lipid homeostasis in the face of chronic ER stress and lipotoxicity.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

Effect of nighttime light exposure on glucose metabolism in protein-restricted mice.

2021 ◽  
Author(s):  
Patricia Cristine Borck ◽  
Sarah Rickli ◽  
Jean Franciesco Vettorazzi ◽  
Thiago Martins Batista ◽  
Antonio Carlos Boschero ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glucose Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Metabolic Diseases ◽  
Light Exposure ◽  
Biological Rhythms ◽  
Fibroblast Growth Factor 21 ◽  
Low Protein ◽  
Nighttime Light ◽  
Fgf21 Expression

Disruption of biological rhythms due exposure to artificial light at night (ALAN) has been emerged as new risk factor for metabolic diseases. However, it remains largely unexplored the effects induced by exposure to ALAN on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance. Objective: Here we evaluate whether low-protein diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a low-protein (LP) diet and housed on 12h light/dark (L/D) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/dark cycle or exposed to ALAN for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN lead to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly the insulin resistance developed in mice exposed to ALAN was diet-dependent. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of Phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of Fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation on hepatic Fgf21 expression.

scholarly journals Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78-Loaded Extracellular Vesicles

2020 ◽  
Author(s):  
Malgorzata Furmanik ◽  
Rick van Gorp ◽  
Meredith Whitehead ◽  
Sadia Ahmad ◽  
Jayanta Bordoloi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Er Stress ◽  
Vascular Calcification ◽  
Bone Mineralization ◽  
Extracellular Vesicle ◽  
Dependent Manner ◽  
The Matrix ◽  
Stress Dependent

Objective: Vascular calcification is common among aging populations and mediated by vascular smooth muscle cells (VSMCs). The endoplasmic reticulum (ER) is involved in protein folding and ER stress has been implicated in bone mineralization. The role of ER stress in VSMC-mediated calcification is less clear. Approach and Results: mRNA expression of the ER stress markers PERK (PKR (protein kinase RNA)-like ER kinase), ATF (activating transcription factor) 4, ATF6, and Grp78 was detectable in human vessels with levels of PERK decreased in calcified plaques compared to healthy vessels. Protein deposition of Grp78/Grp94 was increased in the matrix of calcified arteries. Induction of ER stress accelerated human primary VSMC-mediated calcification, elevated expression of some osteogenic markers (Runx2, Osterix, ALP, BSP, and OPG), and decreased expression of SMC markers. ER stress potentiated extracellular vesicle (EV) release via SMPD3. EVs from ER stress-treated VSMCs showed increased Grp78 levels and calcification. Electron microscopy confirmed the presence of Grp78/Grp94 in EVs. siRNA knock-down of Grp78 decreased calcification. Warfarin-induced Grp78 and ATF4 expression in rat aortas and VSMCs and increased calcification in an ER stress-dependent manner via increased EV release. Conclusions: ER stress induces vascular calcification by increasing release of Grp78-loaded EVs. Our results reveal a novel mechanism of action of warfarin, involving increased EV release via the PERK-ATF4 pathway, contributing to calcification. This study is the first to show that warfarin induces ER stress and to link ER stress to cargo loading of EVs.

scholarly journals The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

2020 ◽  
Vol 21 (6) ◽  
pp. 2108 ◽  
Author(s):  
Wioletta Rozpędek-Kamińska ◽  
Natalia Siwecka ◽  
Adam Wawrzynkiewicz ◽  
Radosław Wojtczak ◽  
Dariusz Pytel ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Stress Conditions ◽  
World Population ◽  
Dependent Manner ◽  
Age Related ◽  
The Unfolded Protein Response

Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism—accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.

scholarly journals Tunicamycin-Induced Endoplasmic Reticulum Stress Mediates Mitochondrial Dysfunction in Human Adipocytes

2020 ◽  
Vol 105 (9) ◽  
pp. 2905-2918
Author(s):  
Laura Jackisch ◽  
Alice M Murphy ◽  
Sudhesh Kumar ◽  
Harpal Randeva ◽  
Gyanendra Tripathi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Oxidative Capacity ◽  
Basal Respiration ◽  
Dependent Manner ◽  
Human Adipocytes ◽  
Mitochondrial Fragmentation ◽  
Dynamic Relationship ◽  
Obese Subjects

Abstract Context Dysfunctional endoplasmic reticulum (ER) and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date, insight into this dynamic relationship has not been characterized in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants. Methods Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP), and dynamics. Results ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24 h: 23%↑; 48 h: 68%↑, P < 0.001; 72 h: 136%↑, P < 0.001). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganization of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (P < 0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, P < 0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity. Conclusion These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess–induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.

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