Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs

2005 ◽  
Vol 289 (1) ◽  
pp. G54-G63 ◽  
Author(s):  
Farah Esfandiari ◽  
Jesus A. Villanueva ◽  
Donna H. Wong ◽  
Samuel W. French ◽  
Charles H. Halsted
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Fatty Acid Synthase ◽  
Hepatic Injury ◽  
Folate Deficiency ◽  
Signal Pathways ◽  
Mrna Levels ◽  
Caspase 12 ◽  
Ethanol Feeding ◽  
Stress Signals

Previously, we showed that feeding micropigs ethanol with a folate-deficient diet promoted the development of hepatic injury while increasing hepatic levels of homocysteine and S-adenosylhomocysteine (SAH) and reducing the level of S-adenosylmethionine (SAM) and the SAM-to-SAH ratio. Our present goals were to evaluate mechanisms for hepatic injury using liver specimens from the same micropigs. The effects of ethanol feeding or folate-deficient diets, singly or in combination, on cytochrome P-450 2E1 (CYP2E1) and signal pathways for apoptosis and steatosis were analyzed using microarray, real-time PCR, and immunoblotting techniques. Apoptosis was increased maximally by the combination of ethanol feeding and folate deficiency and was correlated positively to liver homocysteine and SAH. Liver CYP2E1 and the endoplasmic reticulum stress signals glucose-regulated protein 78 (GRP78), caspase 12, and sterol regulatory element binding protein-1c (SREBP-1c) were each activated in pigs fed folate-deficient or ethanol diets singly or in combination. Liver mRNA levels of CYP2E1, GRP78, and SREBP-1c, and protein levels of CYP2E1, GRP78, nuclear SREBP, and activated caspase 12 each correlated positively to liver levels of SAH and/or homocysteine and negatively to the SAM-to-SAH ratio. The transcripts of the lipogenic enzymes fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase were elevated in the ethanol-fed groups, and each was positively correlated to liver homocysteine levels. The induction of abnormal hepatic methionine metabolism through the combination of ethanol feeding with folate deficiency is associated with the activation of CYP2E1 and enhances endoplasmic reticulum stress signals that promote steatosis and apoptosis.

scholarly journals Chronic Microcystin-LR Exposure Induces Abnormal Lipid Metabolism via Endoplasmic Reticulum Stress in Male Zebrafish

Toxins ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 107 ◽  
Author(s):  
Dandan Zhang ◽  
Wang Lin ◽  
Yinjie Liu ◽  
Honghui Guo ◽  
Lingkai Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Metabolism ◽  
Endoplasmic Reticulum Stress ◽  
Fatty Acid Synthase ◽  
Prolonged Exposure ◽  
Signal Molecules ◽  
Signal Pathways ◽  
Mrna Levels ◽  
Related Factors ◽  
Hepatic Lipid

In order to explore effects of low levels of continuous microcystin-LR (MC-LR) (a cyanotoxin) exposure on hepatic lipid metabolism on the basis of the endoplasmic reticulum stress (ERS) pathway, we exposed adult male zebrafish to MC-LR (0, 1, 5, and 25 μg/L) for 60 days, and hepatic histopathology as well as lipid metabolic parameters were determined with mRNA levels of ERS signal molecules and downstream factors, along with genes associated with lipid metabolism in zebrafish liver. The results revealed that prolonged exposure to MC-LR remarkably altered the levels of hepatic total cholesterol and triglyceride and led to hepatic steatosis, which was also confirmed by hepatic cytoplasmic vacuolization in Hematoxylin/eosin (H&E) stain and lipid droplet accumulation in Oil Red O stain. The severity of hepatic damage and lipidation was increased in a dose-related manner. MC-LR exposure significantly upregulated transcriptional levels of ERS markers including hspa5, mapk8, and chop, indicating the occurrence of ERS in the liver of zebrafish. Concurrently, MC-LR significantly improved mRNA expression of unfolded protein response (UPR) pathway-related genes including atf6, eif2ak3, ern1, and xbp1s, suggesting that all of the three UPR branches were activated by MC-LR. MC-LR also induced significant upregulation of downstream lipid metabolism-related factors and genes including srebf1, srebf2, fatty acid synthase (fasn), acetyl-CoA carboxylase (acaca), stearoyl-CoA desaturase (scd), HMG CoA reductase (hmgcra), and HMG CoA synthase (hmgcs1), and downregulation of genes associated with lipolysis such as triglyceride hydrolase gene (atgl), hormone-sensitive enzyme gene (hsla), and carnitine palmitoyltransferase gene (cpt1aa). Our present results indicated that the cause of hepatic lipid accumulation by MC-LR was mainly by upregulating lipogenic and cholesterol genes but downregulating the expression of lipolytic genes through the induction of srebf1 and srebf2, which were involved in the activation of ERS signal pathways.

scholarly journals Exogenous acylated ghrelin promotes but un-acylated ghrelin prevents hepatic steatosis by modulating peripheral insulin resistance and hepatic oxidative and endoplasmic reticulum stress

2021 ◽  
Vol 7 (3) ◽  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
Lipid Synthesis ◽  
Acylated Ghrelin ◽  
Mrna Levels ◽  
Protein Levels

Objectives: This study tested the effects of acylated (AG and un-acylated ghrelin (UAG) on hepatic lipid synthesis and insulin resistance (IR) from prospective to their effect on endoplasmic reticulum stress and investigated the possible underlying mechanisms. Methods: Healthy rats were divided as 4 groups (n=12/each) as control, control + AG, control + UAG, and control + AG + UAG (1:1). GA or UAG were given subcutaneously (200 ng/kg/each) for 8 weeks. Results: AG increased fasting levels of glucose and insulin resistance, increased hepatic glucose production, and impaired glucose and insulin tolerance. Besides, it increased serum levels of free fatty acids (FFAs), enhanced serum and hepatic levels of triglycerides and cholesterol, and increased lipid deposition in the livers of rats. Concomitantly, it stimulated the mRNA levels of SREBP1/2, fatty acid synthase, and protein levels of all arms of ER stress including Xbp-1, CHOP, ATF-6, and p-eIF2α, thus activating lipid synthesis and ER stress. It also reduced protein levels of p-IRS (Tyr612), p-Akt (Ser307), and increased levels of ROS, TNF-α, IL-6, and protein levels of cleaved caspase-12, p-IRS (Ser307), and p-JNK (The183/Tyr186) in rats’ livers. Administration of UAG alone or in combination with AG produced contradictory effects. However, both AG and UAG significantly increased mRNA levels of AMPK and PPARα suggesting FAs oxidation. Conclusion: AG induces hepatic steatosis and suppresses hepatic insulin signaling mainly by inducing peripheral IR that is associated with hepatic oxidative stress, inflammation, and ER stress. However, UAG alone or in combination exerts opposite effects.

scholarly journals Dahuang Danshen Decoction Inhibits Pancreatic Fibrosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xiaoqiang Liang ◽  
Mian Han ◽  
Xuelin Zhang ◽  
Xun Sun ◽  
Kui Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Molecular Docking ◽  
Endoplasmic Reticulum Stress ◽  
Serum Levels ◽  
Pancreatic Fibrosis ◽  
Mrna Levels ◽  
Antioxidant Genes ◽  
Caspase 12

Background. In Traditional Chinese Medicine (TCM), Dahuang Danshen decoction (DD) is used to treat pancreatic fibrosis. Pancreatic fibrosis is a typical manifestation of chronic pancreatitis (CP), which affects the digestive system. The therapeutic mechanisms of DD in pancreatic fibrosis are unclear. Aim. This study aimed to investigate the regulatory mechanisms of DD on oxidative stress and endoplasmic reticulum stress in CP. Materials and Methods. Experimental rats were intraperitoneally injected with 500 mg/kg BW of diethyldithiocarbamate (DDC) twice a week for six weeks to induce CP. At the same time, DD was administered orally at daily doses of 1.37 g/kg BW, 2.74 g/kg BW, and 5.48 g/kg BW to evaluate its treatment effects on CP. After all treatments, pancreatic tissues were harvested and subjected to H&E staining. Transmission electron microscopy (TEM) was also performed to show the endoplasmic reticulum structure in the pancreatic tissues. Immunohistochemistry was used to detect the α-SMA expression level in the pancreatic tissues. Metabolomics analysis of the serum and proteomics analysis of the pancreatic tissues were performed to reveal the changes of endogenous metabolites and proteins, respectively. Concentrations of GSH, MDA, SOD, ROS, col-1, and col-3 were determined using corresponding kits. The western blotting method was used to determine the protein levels of Keap-1, HO-1, NQO1, Nrf2, GRP, JNK, and caspase 12. The pancreatic mRNA levels of NQO1, GPX1, HO-1, GST-π, GRP, JNK, and caspase 12 were also determined by quantitative PCR. The interactions between TCM components and Keap-1 were investigated by molecular docking modeling. Results. The pathohistological results demonstrated that DD could ameliorate DDC-induced CP in vivo, indicated by reduction of α-SMA, col-1, col-3, TNF-α, and IL-6. DD increased serum levels of GSH and SOD but reduced pancreatic ROS. DD decreased cytoplasmic Keap-1 and increased Nrf2 nuclear localization. Correspondingly, DD increased the expression levels of Nrf2 downstream antioxidant genes NQO1, GPX1, HO-1, and GST-π. DD also decreased ERS hallmarks caspase 12 cleavage and GRP expression. Eventually, DD inhibited PSC activation by reducing JNK phosphorylation and MMK-3/p38 expression. Molecular docking analysis showed that salvianolic acid B and emodin had a good binding affinity toward Keap-1. Conclusions. These results demonstrated that DD could ameliorate the oxidative and endoplasmic reticulum stress through releasing Nrf2 from Keap-1 binding and inducing the downstream antioxidant enzymes. As a result, DD could thwart pancreatic fibrosis by inhibiting PSCs activation, which was induced by OS and ERS through JNK and MMK3/p38 pathways.

scholarly journals The Sodium-Glucose Co-Transporter 2 Inhibitor, Empagliflozin, Protects against Diabetic Cardiomyopathy by Inhibition of the Endoplasmic Reticulum Stress Pathway

2017 ◽  
Vol 41 (6) ◽  
pp. 2503-2512 ◽  
Author(s):  
Yang Zhou ◽  
Wei Wu
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Diabetic Cardiomyopathy ◽  
Left Ventricular ◽  
High Dose ◽  
Mrna Levels ◽  
Caspase 12 ◽  
Endoplasmic Reticulum Stress Pathway ◽  
Systolic And Diastolic Function ◽  
Stress Pathway

Background/Aims: This study aimed to determine whether or not the sodium-glucose co-transporter 2 inhibitor, empagliflozin (EMPA), can protect against diabetic cardiomyopathy (DCM) and to elucidate the related mechanism. Methods: Rats were divided into the following four groups: a non-diabetic group; diabetic cardiomyopathy rats without EMPA treatment; and diabetic cardiomyopathy rats with EMPA treatment (low- and high-dose EMPA). Hemodynamic measurements were performed to evaluate left ventricular systolic and diastolic function. The histopathology of the heart was examined with hematoxylin-eosin staining. Expression of glucose-regulated protein (GRP)78, enhancer-binding protein homologous protein (CHOP), and caspase-12 was detected by Western blot, and the mRNA levels of XBP1, ATF4, and TRAF2 were analysed by real-time PCR. Results: EMPA significantly decreased the blood glucose level when compared with vehicle. EMPA strongly improved cardiac function based on hemodynamic and histopathologic analyses. Moreover, EMPA can significantly down-regulate the expression of GRP78, CHOP, and caspase-12 (P < 0.01). Additionally, the mRNA levels of XBP1, ATF4, and TRAF2 were markedly decreased by administration of EMPA (P < 0.01). Conclusion: EMPA protects against DCM by inactivating the endoplasmic reticulum stress pathway.

scholarly journals Ginkgo biloba Leaf Extract Protects against Myocardial Injury via Attenuation of Endoplasmic Reticulum Stress in Streptozotocin-Induced Diabetic ApoE−/− Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Jinfan Tian ◽  
Yanfei Liu ◽  
Yue Liu ◽  
Keji Chen ◽  
Shuzheng Lyu
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Myocardial Injury ◽  
Caspase 3 ◽  
Interstitial Fibrosis ◽  
Serum Levels ◽  
Cardiomyocyte Apoptosis ◽  
Mrna Levels ◽  
Caspase 12 ◽  
Apoptosis Pathways

Diabetes was induced in high-fat diet-fed ApoE−/− mice via administration of low-dose streptozotocin (STZ) for five days. Mice were then treated with GBE (200 or 400 mg/kg) by gastric gavage daily for 12 weeks. Mice in the untreated diabetic group received saline instead, and nondiabetic C57BL/6J mice served as controls. Collagen І and ІІІ mRNA expression was measured by real-time PCR. TNF-α, IL-1β mRNA levels, and NF-κB expression were determined to analyze intramyocardial inflammation. Hallmarks of endoplasmic reticulum stress- (ERS-) related apoptosis pathways, including phosphorylated c-Jun N-terminal kinase (p-JNK), C/EBP homologous protein (CHOP), caspase-12, and cleaved caspase-3, were analyzed by Western blotting. Diabetic ApoE−/− myocardial injury was associated with increased cardiomyocyte apoptosis (increased expression of p-JNK, CHOP, caspase-12, and cleaved caspase-3), interstitial fibrosis (increased mRNA levels of collagen І and ІІІ), and inflammation (increased mRNA levels of TNF-α and IL-1β, and NF-κB expression). GBE at 200 and 400 mg/kg/day significantly attenuated cardiomyocyte apoptosis, collagen deposition, and inflammation in diabetic mice via inhibition of the p-JNK, CHOP, and caspase-12 pathways. Serum levels of the proinflammatory cytokines (IL-6, IL-1β, and TNF-α), blood glucose, and lipid profiles were also regulated by GBE treatment. GBE might be beneficial in the treatment of diabetic myocardial injury.

scholarly journals Excessive training is associated with endoplasmic reticulum stress but not apoptosis in the hypothalamus of mice

2017 ◽  
Vol 42 (4) ◽  
pp. 354-360 ◽  
Author(s):  
Ana Paula Pinto ◽  
Alisson Luiz da Rocha ◽  
Bruno Cesar Pereira ◽  
Luciana da Costa Oliveira ◽  
Gustavo Paroschi Morais ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Downhill Running ◽  
Stress Markers ◽  
Caspase 12 ◽  
Tnf Α

Downhill running-based overtraining model increases the hypothalamic levels of IL-1β, TNF-α, SOCS3, and pSAPK-JNK. The aim of the present study was to verify the effects of 3 overtraining protocols on the levels of BiP, pIRE-1 (Ser724), pPERK (Thr981), pelF2α (Ser52), ATF-6, GRP-94, caspase 4, caspase 12, pAKT (Ser473), pmTOR (Ser2448), and pAMPK (Thr172) proteins in the mouse hypothalamus. The mice were randomized into the control, overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up), and overtrained by running without inclination (OTR) groups. After the overtraining protocols (i.e., at the end of week 8), hypothalamus was removed and used for immunoblotting. The OTR/down group exhibited increased levels of all of the analyzed endoplasmic reticulum stress markers in the hypothalamus at the end of week 8. The OTR/up and OTR groups exhibited increased levels of BiP, pIRE-1 (Ser724), and pPERK (Thr981) in the hypothalamus at the end of week 8. There were no significant differences in the levels of caspase 4, caspase 12, pAKT (Ser473), pmTOR (Ser2448), and pAMPK (Thr172) between the experimental groups at the end of week 8. In conclusion, the 3 overtraining protocols increased the endoplasmic reticulum stress at the end of week 8.

scholarly journals Ginsenoside Rg1 Prevents Doxorubicin-Induced Cardiotoxicity through the Inhibition of Autophagy and Endoplasmic Reticulum Stress in Mice

2018 ◽  
Vol 19 (11) ◽  
pp. 3658 ◽  
Author(s):  
Zhi-Meng Xu ◽  
Cheng-Bin Li ◽  
Qing-Ling Liu ◽  
Ping Li ◽  
Hua Yang
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Role ◽  
Primary Component ◽  
Signal Pathways ◽  
Ginsenoside Rg1 ◽  
Cellular Signal ◽  
Pre Treatment ◽  
Activating Transcription Factor ◽  
Doxorubicin Group

Ginsenoside Rg1, a saponin that is a primary component of ginseng, has been demonstrated to protect hearts from diverse cardiovascular diseases with regulating multiple cellular signal pathways. In the present study, we investigated the protective role of ginsenoside Rg1 on doxorubicin-induced cardiotoxicity and its effects on endoplasmic reticulum stress and autophagy. After pre-treatment with ginsenoside Rg1 (50 mg/kg i.g.) for 7 days, male C57BL/6J mice were intraperitoneally injected with a single dose of doxorubicin (6 mg/kg) every 3 days for four injections. Echocardiographic and pathological findings showed that ginsenoside Rg1 could significantly reduce the cardiotoxicity induced by doxorubicin. Ginsenoside Rg1 significantly inhibited doxorubicin-induced formation of autophagosome. At the same time, ginsenoside Rg1 decreased the doxorubicin-induced cardiac microtubule-associated protein-light chain 3 and autophagy related 5 expression. Ginsenoside Rg1 can reduce endoplasmic reticulum dilation caused by doxorubicin. Compared with the doxorubicin group, the expression of cleaved activating transcription factor 6 and inositol-requiring enzyme 1 decreased in group ginsenoside Rg1. Treatment with ginsenoside Rg1 reduces the expression of TIF1 and increases the expression of glucose-regulated protein 78. In the ginsenoside Rg1 group, the expression of p-P70S6K, c-Jun N-terminal kinases 1 and Beclin1 declined. These results indicate that ginsenoside Rg1 may improve doxorubicin-induced cardiac dysfunction by inhibiting endoplasmic reticulum stress and autophagy.

Increased expression of endoplasmic reticulum stress-related caspase-12 and CHOP in the hippocampus of EAE mice

2019 ◽  
Vol 147 ◽  
pp. 174-182 ◽  
Author(s):  
Maryam Kamarehei ◽  
Sussan Kabudanian Ardestani ◽  
Masoumeh Firouzi ◽  
Hamid Zahednasab ◽  
Hossein Keyvani ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Caspase 12
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