scholarly journals Lipid-Induced Endoplasmic Reticulum Stress in Liver Cells Results in Two Distinct Outcomes: Adaptation with Enhanced Insulin Signaling or Insulin Resistance

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2164-2177 ◽  
Author(s):  
Caroline S. Achard ◽  
D. Ross Laybutt
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Insulin Signaling ◽  
Hepg2 Cells ◽  
Glycogen Synthesis ◽  
Liver Cells ◽  
Dependent Manner ◽  
Akt Phosphorylation ◽  
High Level

Chronically elevated fatty acids contribute to insulin resistance through poorly defined mechanisms. Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in lipid-induced insulin resistance. However, the UPR is also a fundamental mechanism required for cell adaptation and survival. We aimed to distinguish the adaptive and deleterious effects of lipid-induced ER stress on hepatic insulin action. Exposure of human hepatoma HepG2 cells or mouse primary hepatocytes to the saturated fatty acid palmitate enhanced ER stress in a dose-dependent manner. Strikingly, exposure of HepG2 cells to prolonged mild ER stress activation induced by low levels of thapsigargin, tunicamycin, or palmitate augmented insulin-stimulated Akt phosphorylation. This chronic mild ER stress subsequently attenuated the acute stress response to high-level palmitate challenge. In contrast, exposure of HepG2 cells or hepatocytes to severe ER stress induced by high levels of palmitate was associated with reduced insulin-stimulated Akt phosphorylation and glycogen synthesis, as well as increased expression of glucose-6-phosphatase. Attenuation of ER stress using chemical chaperones (trimethylamine N-oxide or tauroursodeoxycholic acid) partially protected against the lipid-induced changes in insulin signaling. These findings in liver cells suggest that mild ER stress associated with chronic low-level palmitate exposure induces an adaptive UPR that enhances insulin signaling and protects against the effects of high-level palmitate. However, in the absence of chronic adaptation, severe ER stress induced by high-level palmitate exposure induces deleterious UPR signaling that contributes to insulin resistance and metabolic dysregulation.

scholarly journals Polyhexamethyleneguanidine Phosphate-Induced Cytotoxicity in Liver Cells Is Alleviated by Tauroursodeoxycholic Acid (TUDCA) via a Reduction in Endoplasmic Reticulum Stress

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1023 ◽  
Author(s):  
Sou Hyun Kim ◽  
Doyoung Kwon ◽  
Seunghyun Lee ◽  
Sung Hwan Ki ◽  
Hye Gwang Jeong ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Hepg2 Cells ◽  
Apoptotic Cell ◽  
Liver Cells ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
Tauroursodeoxycholic Acid ◽  
Chemical Chaperone

Polyhexamethyleneguanidine phosphate (PHMG-P) is a widely used polymeric antimicrobial agent known to induce significant pulmonary toxicity. Several studies have reported that the liver also can be a target organ of polyhexamethyleneguanidine (PHMG) toxicity, but the exact effect of this compound on liver cells is not well understood. To identify the mechanism of PHMG hepatotoxicity, HepG2 cells were exposed to PHMG-P for 72 h. The cell viability was significantly decreased by PHMG-P in a time- and concentration-dependent manner. The mitochondrial membrane potential was markedly reduced by PHMG-P and the apoptotic signaling cascade was activated. The increases observed in C/EBP homologous protein (CHOP), p-IRE, and p-JNK levels in PHMG-P-treated cells indicated the induction of endoplasmic reticulum stress. To verify the role of ER stress in PHMG-P-induced cytotoxicity, HepG2 cells were pretreated with the chemical chaperone, tauroursodeoxycholic acid (TUDCA) and then co-treated with TUDCA and PHMG-P for 24 h. Interestingly, TUDCA inhibited PHMG-P-induced ER stress and cytotoxicity in a dose-dependent manner. The apoptotic cell death and mitochondrial depolarization were also prevented by TUDCA. The proteins involved in the apoptotic pathway were all normalized to their control levels in TUDCA-treated cells. In conclusion, the results suggest that PHMG-P induced significant cytotoxicity in liver cells and ER stress-mediated apoptosis, which may be an important mechanism mediating this hepatotoxicity.

scholarly journals Palmitate Attenuates Insulin Signaling and Induces Endoplasmic Reticulum Stress and Apoptosis in Hypothalamic Neurons: Rescue of Resistance and Apoptosis through Adenosine 5′ Monophosphate-Activated Protein Kinase Activation

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 576-585 ◽  
Author(s):  
Christopher M. Mayer ◽  
Denise D. Belsham
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Insulin Signaling ◽  
Caspase 3 ◽  
Saturated Fatty Acids ◽  
Amp Kinase ◽  
Hypothalamic Neurons ◽  
Peripheral Tissues ◽  
Short Term Exposure

Hypothalamic insulin signaling is essential to the maintenance of glucose and energy homeostasis. During pathological states, such as obesity and type 2 diabetes mellitus, insulin signaling is impaired. One key mechanism involved in the development of insulin resistance is lipotoxicity, through increased circulating saturated fatty acids. Although many studies have begun to determine the underlying mechanisms of lipotoxicity in peripheral tissues, little is known about the effects of excess lipids in the brain. We used a hypothalamic, neuronal cell model, mHypoE-44, to understand how the highly prevalent nonesterified fatty acid, palmitate, affects neuronal insulin signaling. Through Western blot analysis, we discerned that prolonged exposure to palmitate impairs insulin activation, as assessed by phosphorylation of Akt. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cellular insulin resistance and apoptosis in peripheral tissues. Palmitate treatment induced ER stress through a c-Jun N-terminal kinase (JNK)-dependent pathway because a selective JNK inhibitor blocked palmitate activation of the ER stress pathways eIF2α and X-box binding protein-1. Interestingly, JNK inhibition did not prevent the palmitate-mediated cleaved caspase-3 increase, an apoptotic marker, or insulin signaling attenuation. However, pretreatment with the AMP kinase activator, aminoimidazole carboxamide ribonucleotide, blocked JNK phosphorylation and importantly prevented caspase-3 cleavage and restored insulin signaling during short-term exposure to palmitate. Thus, activation of AMP kinase prevents the deleterious effects of palmitate on hypothalamic neurons by inhibiting the onset of insulin resistance and apoptosis.

scholarly journals Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2206-2218 ◽  
Author(s):  
Gong Peng ◽  
Linghai Li ◽  
Yanbo Liu ◽  
Jing Pu ◽  
Shuyan Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Insulin Sensitivity ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Dietary Fatty Acids ◽  
Akt Phosphorylation ◽  
Stress Relieving

Pathological elevation of plasma fatty acids reduces insulin sensitivity. Although several regulation pathways have been reported, the molecular mechanisms of insulin sensitivity remain elusive, especially in skeletal muscle where most glucose is consumed. This study focuses on how two major dietary fatty acids affect insulin signaling in skeletal muscle cells. Palmitic acid (PA) not only reduced insulin-stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress. Relieving ER stress using 4-phenyl butyric acid blocked PA-mediated protein kinase R-like ER kinase phosphorylation and ER expansion and reversed the inhibitory effect of PA on insulin-stimulated Akt phosphorylation. Importantly, oleic acid (OA) could also recover PA-reduced Akt phosphorylation and abolish both PA-mediated ER expansion and ER stress. The competition between these two fatty acids was further verified in rat skeletal muscle using venous fatty acid infusion. 3H-labeled PA was converted mainly to active lipids (phospholipids and diacylglycerol) in the absence of OA, but to triacylglycerol in the presence of OA. Subcellular triacylglycerol and adipocyte differentiation-related protein from PA-treated cells cofractionated with the ER in the absence of OA but switched to the low-density fraction in the presence of OA. Taken together, these data suggest that the PA-mediated lipid composition and localization may cause ER expansion and consequently cause ER stress and insulin resistance in skeletal muscle.

scholarly journals Fibroblast growth factor 21 reverses suppression of adiponectin expression via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice

2016 ◽  
Vol 242 (4) ◽  
pp. 441-447 ◽  
Author(s):  
Qinyue Guo ◽  
Lin Xu ◽  
Jiali Liu ◽  
Huixia Li ◽  
Hongzhi Sun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Growth Factor ◽  
Er Stress ◽  
Insulin Signaling ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Obese Mice

Fibroblast growth factor 21 (FGF21) has recently emerged as a novel endocrine hormone involved in the regulation of glucose and lipid metabolism. However, the exact mechanisms whereby FGF21 mediates insulin sensitivity remain not fully understood. In the present study, FGF21was administrated in high-fat diet-induced obese mice and tunicamycin-induced 3T3-L1 adipocytes, and metabolic parameters, endoplasmic reticulum (ER) stress indicators, and insulin signaling molecular were assessed by Western blotting. The administration of FGF21 in obese mice reduced body weight, blood glucose and serum insulin, and increased insulin sensitivity, resulting in alleviation of insulin resistance. Meanwhile, FGF21 treatment reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress in adipose tissue of obese mice. Additionally, suppression of ER stress via the ER stress inhibitor tauroursodeoxycholic acid increased adiponectin expression and improved insulin resistance in obese mice and in tunicamycin-induced adipocytes. In conclusion, our results showed that the administration of FGF21 reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress under the condition of insulin resistance, demonstrating the causative role of ER stress in downregulating adiponectin levels.

scholarly journals The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

2020 ◽  
Vol 11 ◽  
Author(s):  
Han Cheng ◽  
Xiaokun Gang ◽  
Guangyu He ◽  
Yujia Liu ◽  
Yingxuan Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Insulin Signaling ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Glucose Sensing ◽  
Hepatic Insulin Resistance ◽  
Endoplasmic Reticulum Membrane ◽  
Hepatic Insulin Signaling

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

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.

Vascular insulin resistance related to endoplasmic reticulum stress in aortas from a rat model of chronic kidney disease

2012 ◽  
Vol 303 (9) ◽  
pp. H1154-H1165 ◽  
Author(s):  
Qiu Gen Zhou ◽  
Xiao Jing Fu ◽  
Guo Yu Xu ◽  
Wei Cao ◽  
Hong Fa Liu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Chronic Kidney Disease ◽  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Serine Phosphorylation

Metabolic insulin resistance has been demonstrated in patients with nondiabetic chronic kidney disease (CKD), yet their vascular insulin signaling remains poorly understood. Here we tested the hypothesis that vascular insulin signaling was impaired and related with endoplasmic reticulum (ER) stress in aortas from the reduced renal mass (RRM) model of CKD. The activity of insulin signaling and markers of ER were determined in aortas from rats with RRM and cultured human umbilical vein endothelial cells. Tyrosine phosphorylation of insulin receptor-β and insulin receptor substrate (IRS)-1 and phosphorylation of protein kinase B and endothelial nitric oxide synthase were all decreased in aorta from RRM rats, whereas serine phosphorylation of IRS-1, a marker of insulin resistance, was increased. In addition, nitric oxide generation and insulin-mediated vasorelaxation were decreased in aortas from RRM rats. Insulin signaling in cultured vascular endothelial cells was impaired by induction of ER stress and was restored in aortas of RRM rats by inhibition of ER stress. Taken together, rats with RRM had vascular insulin resistance that was linked to ER stress. This identified vascular insulin resistance and ER stress as a potential therapeutic target for cardiovascular complications in patients with CKD.

scholarly journals Procyanidin B2 Alleviates Palmitic Acid-Induced Injury in HepG2 Cells via Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Yi-Ming Li ◽  
Shao-Yang Zhao ◽  
Huan-Huan Zhao ◽  
Bao-Hua Wang ◽  
Sai-Mei Li
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Hepg2 Cells ◽  
Cellular Injury ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Protein Levels ◽  
Caspase 1 ◽  
The Metabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome featuring ectopic lipid accumulation in hepatocytes. NAFLD has been a severe threat to humans with a global prevalence of over 25% yet no approved drugs for the treatment to date. Previous studies showed that procyanidin B2 (PCB2), an active ingredient from herbal cinnamon, has an excellent hepatoprotective effect; however, the mechanism remains inconclusive. The present study aimed to investigate the protective effect and underlying mechanism of PCB2 on PA-induced cellular injury in human hepatoma HepG2 cells. Our results showed that PA-induced oxidative stress, calcium disequilibrium, and subsequent endoplasmic reticulum stress (ERS) mediated cellular injury, with elevated protein levels of GRP78, GRP94, CHOP, and hyperphosphorylation of PERK and IRE1α as well as the increased ratio of Bax/Bcl-2, which was restored by PCB2 in a concentration-dependent manner, proving the excellent antiapoptosis effect. In addition, 4-phenylbutyric acid (4-PBA), the ER stress inhibitor, increased cell viability and decreased protein levels of GRP78 and CHOP, which is similar to PCB2, and thapsigargin (TG), the ER stress agonist, exhibited conversely meanwhile partly counteracted the hepatic protection of PCB2. What is more, upregulated protein expression of p-IKKα/β, p-NF-κB p65, NLRP3, cleaved caspase 1, and mature IL-1β occurred in HepG2 cells in response to PA stress while rescued with the PCB2 intervention. In conclusion, our study demonstrated that PA induces ERS in HepG2 cells and subsequently activates downstream NLRP3 inflammasome-mediated cellular injury, while PCB2 inhibits NLRP3/caspase 1/IL-1β pathway, inflammation, and apoptosis with the presence of ERS, thereby promoting cell survival, which may provide pharmacological evidence for clinical approaches on NAFLD.

scholarly journals Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates Diet-induced Endoplasmic Reticulum Stress in Liver and Adipose Tissue

2013 ◽  
Vol 288 (20) ◽  
pp. 14189-14199 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Naoto Nagata ◽  
Daniel AbouBechara ◽  
Samah Chahed ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Er Stress ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
High Fat ◽  
Pharmacological Inhibition

Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Herein, we assessed the role of sEH in regulating endoplasmic reticulum (ER) stress in liver and adipose tissue. We report that sEH expression was increased in the livers and adipose tissue of mice fed a high fat diet, the adipose tissue of overweight humans, and palmitate-treated cells. Importantly, sEH deficiency or inhibition in mice attenuated chronic high fat diet-induced ER stress in liver and adipose tissue. Similarly, pharmacological inhibition of sEH in HepG2 cells and 3T3-L1 adipocytes mitigated chemical-induced ER stress and activation of JNK, p38, and cell death. In addition, insulin signaling was enhanced in HepG2 cells treated with sEH substrates and attenuated in cells treated with sEH products. In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity.

scholarly journals PDE5A Suppresses Proteasome Activity Leading to Insulin Resistance in C2C12 Myotubes

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Wei Liu ◽  
Xiaojun Tian ◽  
Ti Wu ◽  
Le Liu ◽  
Yanghongyun Guo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Insulin Signaling ◽  
Specific Protein ◽  
Proteasome Activity ◽  
C2c12 Myotubes ◽  
Akt Phosphorylation ◽  
Phosphorylated Proteins ◽  
Activity Inhibition ◽  
Phosphodiesterase Type

Objective. The involvement of phosphodiesterase type 5 (PDE5) in the development of insulin resistance has been reported recently. However, the underlying molecular mechanism remains unclear. The present study aims at investigating the potential impacts of PDE5A on insulin signaling in C2C12 skeletal muscle myotubes and uncover the related mechanism. Methods. C2C12 myoblasts were differentiated into myotubes. Western blot was performed to detect the levels of proteins and phosphorylated proteins. Glucose uptake was determined by a colorimetric kit. The overexpression or knockdown of specific protein was carried out by infecting the myotubes with adenoviruses carrying cDNA or shRNA corresponding to the targeted protein, respectively. Results. PDE5A was demonstrated to negatively regulate insulin signaling, evidenced by the opposite effects on the suppression or enhancement of the insulin-stimulated Akt phosphorylation and 2-deoxy-D-glucose (2-DG) uptake in C2C12 myotubes, when PDE5A was overexpressed or knockdown, respectively. Interestingly, PDE5A overexpression led to significantly enhanced, while its knockdown resulted in markedly reduced, endoplasmic reticulum (ER) stress. Inhibition of ER stress improved PDE5A overexpression-induced insulin resistance. In addition, PDE5A was found to suppress proteasome activity. Inhibition of PDE5 by its selective inhibitor icariin restored PDE5A overexpression-reduced proteasome activity and mitigated PDE5A overexpression-induced ER stress. Consistently, icariin administration also markedly attenuated the detrimental impacts of PDE5A overexpression on insulin signaling. Conclusions. These results suggest that PDE5A suppresses proteasome activity, which results in ER stress and subsequent insulin resistance in C2C12 myotubes.

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