scholarly journals Mig6 decreases hepatic EGFR activation and survival during saturated fatty acid-induced endoplasmic reticulum stress

2020 ◽  
Author(s):  
Andrew J. Lutkewitte ◽  
Yi-Chun Chen ◽  
Jeffrey L. Hansen ◽  
Patrick T. Fueger
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Er Stress ◽  
Growth Factor Receptor ◽  
Rat Hepatocytes ◽  
Egfr Signaling ◽  
Egfr Expression ◽  
Egfr Activation ◽  
Feedback Inhibitor ◽  
Novel Target

ABSTRACTHyperlipidemia associated with obesity and type 2 diabetes (T2D) promotes excess hepatic lipid storage (steatosis) and endoplasmic reticulum (ER) stress, thereby reducing hepatic cell proliferation and survival. An important receptor tyrosine kinase controlling liver proliferation and survival is the epidermal growth factor receptor (EGFR). EGFR expression and activation are decreased during steatosis in humans and several animal models of obesity. Therefore, restoring EGFR activation in obesity-induced ER stress and diabetes could restore the liver’s capacity for survival and regeneration. As an inducible feedback inhibitor of EGFR activity, mitogen-inducible gene 6 (Mig6) is a novel target for enhancing EGFR signaling during diet-induced obesity (DIO) and T2D. Thus, we hypothesized hepatic ER stress induces Mig6 expression and decreases EGFR activation during DIO and diabetes. We identified that Mig6 expression was increased during obesity-induced insulin resistance in C57Bl/6J mice fed a high fat diet. We also discovered that both pharmacological- and fatty acid-driven ER stress increased Mig6 expression and decreased EGF-mediated EGFR activation in primary rat hepatocytes and cell lines. Furthermore, siRNA-mediated Mig6 knockdown restored EGFR signaling and reduced caspase 3/7 activation during ER stress. Therefore, we conclude Mig6 is increased during ER stress in DIO, thereby reducing EGFR activation and enhancing cell death. The implications are the induction of Mig6 during DIO and diabetes may decrease hepatocyte survival, thus hindering cellular repair and regenerative mechanisms.

scholarly journals Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1515
Author(s):  
Keiichiro Okuda ◽  
Atsushi Umemura ◽  
Shiori Umemura ◽  
Seita Kataoka ◽  
Hiroyoshi Taketani ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Public Health Problem ◽  
Egfr Signaling ◽  
Alcoholic Steatohepatitis ◽  
Genetic Mouse Model ◽  
Treatment And Prevention ◽  
Egfr Expression

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

scholarly journals Monounsaturated fatty acid antagonizes saturated fatty acid-induced cardiomyopathy via improving membrane fatty acid composition and endoplasmic reticulum stress

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Y Yamamoto ◽  
J E Endo ◽  
K S Shinmura ◽  
M S Sano ◽  
K F Fukuda
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Er Stress ◽  
Diastolic Dysfunction ◽  
Saturated Fatty Acid ◽  
Diastolic Pressure ◽  
Membrane Fatty Acid ◽  
Membrane Fatty Acid Composition ◽  
Scd1 Expression

Abstract Background Obesity-induced lipotoxicity causes cardiac dysfunction in our modern lifestyle. Previously, we have shown that an increase in cardiomyocyte membrane saturated fatty acid (SFA)/ monounsaturated FA (MUFA) ratio mediates endoplasmic reticulum (ER) stress, which was implicated in the pathogenesis of SFA-induced cardiomyopathy. Furthermore, SFA supressed Sirt1/ stearoyl-CoA desaturase-1 (SCD1, converting enzyme from SFA to MUFA) signaling, which further worsened the membrane SFA/MUFA ratio. Purpose To evaluate the effectiveness of targeting membrane fatty acid composition by MUFA. Methods and results In wild-type mice, 16-weeks SFA-rich high lard diet feeding (HLD) caused activation of PPARα signaling and the accumulation of toxic lipid intermediates (diacylglycerol and ceramide) in the heart to the same extent as a MUFA-rich high olive oil diet feeding (HOD). However, only the HLD impaired Sirt1 activity, SCD1 expression, diastolic function (increased left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure-volume relationship (EDPVR)), and cardiac remodeling (hypertrophy and fibrosis). Lipidome analysis showed that HLD-induced diastolic dysfunction coincided with an increase in membrane SFA/MUFA ratio and ER stress induction. 8-weeks HOD after 8-weeks HLD (HOD switch) showed the same degree of obesity and PPARα activation with 16-weeks HLD. By contrast, HOD switched heart were less severe Sirt1/SCD1 signaling dysregulation, increased in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy (hypertrophy, fibrosis, and diastolic dysfunction) compared to 16-weeks HLD. Moreover, in cardiomyocyte-specific Sirt1 knockout mice, HOD switched heart also showed less severe increase in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy compared to 16-weeks HLD although decreased SCD1 expression was not changed. Conclusions We demonstrated that MUFA-rich diet counteracted SFA-induced Sirt1/SCD1 signaling dysregulation and prevented SFA-induced increase in membrane SFA/MUFA ratio. Hence, MUFA-rich diet antagonized SFA-induced ER stress and cardiomyopathy even if Sirt1 deactivated heart (e.g., aged heart). Targeting the cardiomyocyte membrane SFA/MUFA ratio by MUFA might have a new therapeutic potential for SFA-induced cardiomyopathy. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): JSPS KAKENHI

Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Takehiko Kujiraoka ◽  
Yasushi Satoh ◽  
Makoto Ayaori ◽  
Yasunaga Shiraishi ◽  
Yuko Arai-Nakaya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Metabolic Remodeling ◽  
And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

scholarly journals A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR

2018 ◽  
Vol 21 (6) ◽  
pp. 719-729 ◽  
Author(s):  
Talal F Al-Mayhani ◽  
Richard M Heywood ◽  
Vamsidhara Vemireddy ◽  
Justin D Lathia ◽  
Sara G M Piccirillo ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Hierarchical Organization ◽  
Egfr Signaling ◽  
Resistant Disease ◽  
Egfr Expression ◽  
Ng2 Cells ◽  
Human Gbm ◽  
Rna Knockdown ◽  
Cellular Hierarchy ◽  
Relationship Of

Abstract Background Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2− cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. Methods Single GBM NG2+ and NG2− cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2− cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. Results Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2− or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. Conclusions These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2− cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

scholarly journals Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells

Marine Drugs ◽  
2020 ◽  
Vol 18 (8) ◽  
pp. 399 ◽  
Author(s):  
Chien-Huang Liao ◽  
Yu-Tien Tzeng ◽  
Gi-Ming Lai ◽  
Chia-Lun Chang ◽  
Ming-Hung Hu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Stress Response ◽  
Fish Oil ◽  
Er Stress ◽  
Acquired Resistance ◽  
Omega 3 ◽  
Response Elements ◽  
Omega 3 Fatty Acid ◽  
Gefitinib Resistance

Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated β-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.

scholarly journals Chlamydia pneumoniae infection–induced endoplasmic reticulum stress causes fatty acid–binding protein 4 secretion in murine adipocytes

2020 ◽  
Vol 295 (9) ◽  
pp. 2713-2723 ◽  
Author(s):  
Nirwana Fitriani Walenna ◽  
Yusuke Kurihara ◽  
Bin Chou ◽  
Kazunari Ishii ◽  
Toshinori Soejima ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Er Stress ◽  
Fatty Acid Binding Protein ◽  
Chlamydia Pneumoniae ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

Fatty acid–binding protein 4 (FABP4) is predominantly expressed in adipocytes and macrophages and regulates metabolic and inflammatory pathways. FABP4 is secreted from adipocytes during lipolysis, and elevated circulating FABP4 levels are associated with obesity, metabolic disease, and cardiac dysfunction. We previously reported that the bacterial respiratory pathogen Chlamydia pneumoniae infects murine adipocytes and exploits host FABP4 to mobilize fat and replicate within adipocytes. However, whether C. pneumoniae induces FABP4 secretion from adipocytes has not been determined. Here, we show that FABP4 is actively secreted by murine adipocytes upon C. pneumoniae infection. Chemical inhibition of lipase activity and genetic deficiency of hormone-sensitive lipase blocked FABP4 secretion from C. pneumoniae–infected adipocytes. Mechanistically, C. pneumoniae infection induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), resulting in elevated levels of mitochondrial reactive oxygen species and cytosolic Ca2+. Of note, exposure to a mitochondrial reactive oxygen species–specific scavenger, MitoTEMPO, reduced FABP4 release from C. pneumoniae–infected adipocytes. Furthermore, treatment with azoramide, which protects cells against ER stress, decreased FABP4 release from C. pneumoniae–infected adipocytes. Using gene silencing of CHOP (C/EBP homologous protein), a central regulator of ER stress, we further validated the role of C. pneumoniae infection–induced ER stress/UPR in promoting FABP4 secretion. Overall, these results indicate that C. pneumoniae infection robustly induces FABP4 secretion from adipocytes by stimulating ER stress/UPR. Our findings shed additional light on the etiological link between C. pneumoniae infection and metabolic syndrome.

scholarly journals AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target

1999 ◽  
Vol 338 (3) ◽  
pp. 783-791 ◽  
Author(s):  
Deborah M. MUOIO ◽  
Kimberly SEEFELD ◽  
Lee A. WITTERS ◽  
Rosalind A. COLEMAN
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Rat Hepatocytes ◽  
C2c12 Myotubes ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Triacylglycerol Synthesis ◽  
Skeletal Muscle Lipid ◽  
Novel Target

AMP-activated kinase (AMPK) is activated in response to metabolic stresses that deplete cellular ATP, and in both liver and skeletal muscle, activated AMPK stimulates fatty acid oxidation. To determine whether AMPK might reciprocally regulate glycerolipid synthesis, we studied liver and skeletal-muscle lipid metabolism in the presence of 5-amino-4-imidazolecarboxamide (AICA) riboside, a cell-permeable compound whose phosphorylated metabolite activates AMPK. Adding AICA riboside to cultured rat hepatocytes for 3 h decreased [14C]oleate and [3H]glycerol incorporation into triacylglycerol (TAG) by 50% and 38% respectively, and decreased oleate labelling of diacylglycerol by 60%. In isolated mouse soleus, a highly oxidative muscle, incubation with AICA riboside for 90 min decreased [14C]oleate incorporation into TAG by 37% and increased 14CO2 production by 48%. When insulin was present, [14C]oleate oxidation was 49% lower and [14C]oleate incorporation into TAG was 62% higher than under basal conditions. AICA riboside blocked insulin's antioxidative and lipogenic effects, increasing fatty acid oxidation by 78% and decreasing labelled TAG 43%. Similar results on fatty acid oxidation and acylglycerol synthesis were observed in C2C12 myoblasts, and in differentiated C2C12 myotubes, AICA riboside also inhibited the hydrolysis of intracellular TAG. These data suggest that AICA riboside might inhibit sn-glycerol-3-phosphate acyltransferase (GPAT), which catalyses the committed step in the pathway of glycerolipid biosynthesis. Incubating rat hepatocytes with AICA riboside for both 15 and 30 min decreased mitochondrial GPAT activity 22–34% without affecting microsomal GPAT, diacylglycerol acyltransferase or acyl-CoA synthetase activities. Finally, purified recombinant AMPKα1 and AMPKα2 inhibited hepatic mitochondrial GPAT in a time-and ATP-dependent manner. These data show that AMPK reciprocally regulates acyl-CoA channelling towards β-oxidation and away from glycerolipid biosynthesis, and provide strong evidence that AMPK phosphorylates and inhibits mitochondrial GPAT.

scholarly journals Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma

2011 ◽  
Vol 300 (3) ◽  
pp. L414-L421 ◽  
Author(s):  
Timothy D. Le Cras ◽  
Thomas H. Acciani ◽  
Elizabeth M. Mushaben ◽  
Elizabeth L. Kramer ◽  
Patricia A. Pastura ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Transgenic Mice ◽  
Growth Factor Receptor ◽  
Airway Hyperreactivity ◽  
Egfr Signaling ◽  
Egfr Activation ◽  
Epidermal Growth

Increases in the epidermal growth factor receptor (EGFR) have been associated with the severity of airway thickening in chronic asthmatic subjects, and EGFR signaling is induced by asthma-related cytokines and inflammation. The goal of this study was to determine the role of EGFR signaling in a chronic allergic model of asthma and specifically in epithelial cells, which are increasingly recognized as playing an important role in asthma. EGFR activation was assessed in mice treated with intranasal house dust mite (HDM) for 3 wk. EGFR signaling was inhibited in mice treated with HDM for 6 wk, by using either the drug erlotinib or a genetic approach that utilizes transgenic mice expressing a mutant dominant negative epidermal growth factor receptor in the lung epithelium (EGFR-M mice). Airway hyperreactivity (AHR) was assessed by use of a flexiVent system after increasing doses of nebulized methacholine. Airway smooth muscle (ASM) thickening was measured by morphometric analysis. Sensitization to HDM (IgG and IgE), inflammatory cells, and goblet cell changes were also assessed. Increased EGFR activation was detected in HDM-treated mice, including in bronchiolar epithelial cells. In mice exposed to HDM for 6 wk, AHR and ASM thickening were reduced after erlotinib treatment and in EGFR-M mice. Sensitization to HDM and inflammatory cell counts were similar in all groups, except neutrophil counts, which were lower in the EGFR-M mice. Goblet cell metaplasia with HDM treatment was reduced by erlotinib, but not in EGFR-M transgenic mice. This study demonstrates that EGFR signaling, especially in the airway epithelium, plays an important role in mediating AHR and remodeling in a chronic allergic asthma model.

scholarly journals BIOGENESIS OF ENDOPLASMIC RETICULUM MEMBRANES

1966 ◽  
Vol 30 (1) ◽  
pp. 73-96 ◽  
Author(s):  
Gustav Dallner ◽  
Philip Siekevitz ◽  
George E. Palade
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Rat Hepatocytes ◽  
Liver Fatty Acid ◽  
Adult Liver ◽  
Protein Ratio ◽  
Microsomal Membranes ◽  
Rough Er

The development of the endoplasmic reticulum of rat hepatocytes was studied during a period of rapid cell differentiation, i.e., from 3 days before to 8 days after birth. Before birth, the ER increases in volume, remaining predominantly rough surfaced; after birth, the increase continues but affects mainly the smooth-surfaced part of the system. These changes are reflected in variations of the RNA/protein and PLP/protein ratios of microsomal fractions: the first decreases, while the second increases, with age. The analysis of microsomal membranes and of microsomal lipids indicates that the PLP/protein ratio, the distribution of phospholipids, and the rate of P32 incorporation into these phospholipids show little variation over the period examined and are comparable to values found in adult liver. Fatty acid composition of total phosphatides undergoes, however, drastic changes after birth. During the period of rapid ER development in vivo incorporation of leucine-C14 and glycerol-C14 into the proteins and lipids of microsomal membranes is higher in the rough-than in the smooth-surfaced microsomes, for the first hours after the injection of the label; later on (∼10 hr) the situation is reversed. These results strongly suggest that new membrane is synthesized in the rough ER and subsequently transferred to the smooth ER.

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