POST-BURN HEPATIC INSULIN RESISTANCE IS ASSOCIATED WITH ENDOPLASMIC RETICULUM (ER) STRESS

Background: Obesity is a major risk factor in the development of hepatic insulin resistance, which is characterized by an impairment of insulin ability to inhibit glucose output. Although the underlying mechanism for the link between obesity and insulin resistance in the liver is unclear, it has been widely reported and suggested that hepatic endoplasmic reticulum (ER) stress and inflammation induced by obesity lead to the development of hepatic insulin resistance and gluconeogenesis. Summary: This review addresses the aspects of ER stress and inflammation currently understood to be involved in metabolic disease, including their role in obesity, hepatic insulin resistance, and hyperglycemia.

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

Frontiers in Endocrinology ◽

10.3389/fendo.2020.592129 ◽

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.

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Effect of KCNH6 on Hepatic Endoplasmic Reticulum Stress and Glucose Metabolism

Hormone and Metabolic Research ◽

10.1055/a-1177-6814 ◽

2020 ◽

Vol 52 (09) ◽

pp. 669-675

Author(s):

Jing Lu ◽

Han Shen ◽

Qi Li ◽

Feng-Ran Xiong ◽

Ming-Xia Yuan ◽

...

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Er Stress ◽

Hepatic Insulin Resistance ◽

Glucose Metabolism Disorders ◽

Primary Hepatocytes ◽

Iκb Kinase

AbstractAdult patients with a dysfunctional ether-a-go-go 2 (hERG2) protein, which is encoded by the KCNH6 gene, present with hyperinsulinemia and hyperglycemia. However, the mechanism of KCNH6 in glucose metabolism disorders has not been clearly defined. It has been proposed that sustained endoplasmic reticulum (ER) stress is closely concerned with hepatic insulin resistance and inflammation. Here, we demonstrate that Kcnh6 knockout (KO) mice had impaired glucose tolerance and increased levels of hepatic apoptosis, in addition to displaying an increased insulin resistance that was mediated by high ER stress levels. By contrast, overexpression of KCNH6 in primary hepatocytes led to a decrease in ER stress and apoptosis induced by thapsigargin. Similarly, induction of Kcnh6 by tail vein injection into KO mice improved glucose tolerance by reducing ER stress and apoptosis. Furthermore, we show that KCNH6 alleviated hepatic ER stress, apoptosis, and inflammation via the NFκB-IκB kinase (IKK) pathway both in vitro and in vivo. In summary, our study provides new insights into the causes of ER stress and subsequent induction of primary hepatocytes apoptosis.

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ER Stress Response Failure and Steatohepatitis Comorbid with Diabetes

10.5772/intechopen.100054 ◽

2021 ◽

Author(s):

Takayoshi Sasako ◽

Kohjiro Ueki

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Stress Induction ◽

Er Stress Response ◽

Glucose And Lipid Metabolism ◽

Obesity And Diabetes

Dynamic metabolic changes occur in the liver during the transition between fasting and eating, which is mainly mediated by insulin, a hormone to promote anabolism and suppress catabolism. In obesity and diabetes, insulin resistance is induced via various mechanisms, and among them is endoplasmic reticulum (ER) stress. We recently reported that eating induces transient ER stress and consequent ER stress response in the liver. During eating, expression of Sdf2l1, an ER-resident molecule involved in ER stress-associated degradation, is induced as a part of ER stress response. XBP-1s regulates expression of Sdf2l1 at the transcription level, and Sdf2l1 terminates eating-induced ER stress in the liver, consequently regulating glucose and lipid metabolism. In obesity and diabetes, however, ER stress response is impaired, partly because insulin-mediated translocation of XBP-1s to the nucleus is suppressed, which results in further excessive ER stress. Induction of Sdf2l1 by XBP-1s is highly down-regulated, but restoration of Sdf2l1 ameliorates glucose intolerance and fatty liver. In diabetic patients, hepatic insulin resistance induces enhanced ER stress and ER stress response failure in the liver, which in turn promote hepatic fibrosis and contribute to the development of steatohepatitis comorbid with diabetes.

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12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00373.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. E654-E665 ◽

Cited By ~ 35

Author(s):

Banumathi K. Cole ◽

Norine S. Kuhn ◽

Shamina M. Green-Mitchell ◽

Kendall A. Leone ◽

Rebekah M. Raab ◽

...

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Pancreatic Islets ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Stress Markers ◽

Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

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Cudrania tricuspidatawater extract improved obesity-induced hepatic insulin resistance indb/dbmice by suppressing ER stress and inflammation

Food & Nutrition Research ◽

10.3402/fnr.v59.29165 ◽

2015 ◽

Vol 59 (1) ◽

pp. 29165 ◽

Cited By ~ 8

Author(s):

Ok-Kyung Kim ◽

Da-Eun Nam ◽

Woojin Jun ◽

Jeongmin Lee

Keyword(s):

Insulin Resistance ◽

Er Stress ◽

Hepatic Insulin Resistance

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

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.

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Fenofibrate Ameliorates Insulin Resistance of Lipoprotein Lipase Knockout Heterozygous Mice

10.21203/rs.2.22680/v1 ◽

2020 ◽

Author(s):

Yangxue Li ◽

Tingting Han ◽

Shuang Zheng ◽

Xingxing Ren ◽

Yaomin Hu

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Glucose Tolerance ◽

Er Stress ◽

Lipid Profile ◽

Lipoprotein Lipase ◽

Peroxisome Proliferator ◽

Phosphorylated Akt

Abstract Background The benefits of fenofibrate (FB), a peroxisome proliferator-activated receptor-a agonist, against hyperlipidemia have been established. We investigated the effect of fenofibrate on insulin resistance of lipoprotein lipase knockout heterozygous (LPL+/-) mice, which represent inherited hypertriglyceridemia and impaired glucose tolerance. Methods Male LPL+/- mice were treated with FB (50 mg/kg, once daily) via gavage for 8 weeks. Plasma lipid, glucose tolerance test, systemic insulin sensitivity, insulin signaling of tissues, genes and proteins related to endoplasmic reticulum (ER) stress and oxidative stress were analyzed. Results Body weight of 40-week LPL+/- with FB were reduced by 30.3% (P<0.05), while the differences of 16- and 28-week LPL+/- with FB were not significant (P>0.05). FB improved the lipid profile of both 28 and 40-week LPL+/- (P<0.001 for both), while that of 16-week LPL+/- mice with FB was unaltered (P>0.05). Glucose tolerance of 40-week LPL+/- were improved by FB (P<0.05), while that of 16- and 28-week LPL+/- with FB kept unaltered (P>0.05). Fasting insulin of 40-week LPL +/- were improved by FB (P<0.05), thus HOMA-IR of 40-week LPL+/- was declined (P<0.05). HOMA-IR of 16- and 28-week LPL+/- with FB had no change. Insulin-stimulated phosphorylated Akt (Ser473) in liver and skeletal muscle of 28-week LPL+/- was enhanced by FB (P < 0.001 and P<0.05 respectively). ER stress biomarkers were detected decreased in liver of 16- to 40-week LPL+/- with FB whereas that in muscle of LPL+/- with FB unchanged. Reduced reactive oxygen species (ROS) levels and augmented mRNA expression of superoxide dismutase (SOD) and catalase (CAT) in skeletal muscle of 28- and 40-week LPL+/- mice with FB were observed. There was no significance on ROS levels and mRNA of SOD and CAT in liver between LPL+/- mice with and without FB. Conclusions Fenofibrate improved lipid profile, glucose tolerance, systemic and tissue-specific insulin resistance of LPL knockout heterozygous mice. This may be associated with alleviated endoplasmic reticulum stress in liver and reduced oxidative stress in muscle.

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Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms20071658 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1658 ◽

Cited By ~ 29

Author(s):

Hatem Maamoun ◽

Shahenda Abdelsalam ◽

Asad Zeidan ◽

Hesham Korashy ◽

Abdelali Agouni

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Cardiovascular Disease ◽

Endoplasmic Reticulum ◽

Endothelial Cell ◽

Er Stress ◽

Cardiovascular Complications ◽

Endothelial Cell Dysfunction ◽

Cell Dysfunction ◽

Obesity And Diabetes

Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis.

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Role of O-GlcNAcylation and endoplasmic reticulum stress on obesity and insulin resistance

Turkish Journal of Biochemistry ◽

10.1515/tjb-2018-0303 ◽

2019 ◽

Vol 44 (5) ◽

pp. 599-610 ◽

Cited By ~ 1

Author(s):

Benan Pelin Sermikli ◽

Gulizar Aydogdu ◽

Afsar Abbasi Taghidizaj ◽

Erkan Yilmaz

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Western Blot ◽

Er Stress ◽

Insulin Receptor ◽

Serine Phosphorylation ◽

Wild Type ◽

Adipose Tissues ◽

Insulin Resistant

Abstract Background Obesity is a global public health problem. Obesity closely associated with various metabolic diseases such as; insulin resistance, hypertension, dyslipidemia and cardiovascular diseases. Endoplasmic reticulum (ER) stress is a critical factor for insulin resistance. O-linked N-acetyl-glucosamine (O-GlcNAc); is the post-translational modification which is has a vital role in biological processes; including cell signaling, in response to nutrients, stress and other extracellular stimuli. Materials and methods In this study, we aimed to investigate the role of O-GlcNAc modification in the context of obesity and obesity-associated insulin resistance in adipose tissue. For this purpose, first, the visceral and epididymal adipose tissues of obese and insulin resistant C57BL/6 Lepob/Lepob and wild-type mice were used to determine the O-GlcNAc modification pattern by western blot. Secondly, the external stimulation of O-GlcNAc modification in wild-type mice achieved by intraperitoneal 5 mg/kg/day glucosamine injection every 24 h for 5 days. The effect of increased O-GlcNAc modification on insulin resistance and ER stress investigated in adipose tissues of glucosamine challenged wild-type mice through regulation of the insulin signaling pathway and unfolded protein response (UPR) elements by western blot. In addition to that, the O-GlcNAc status of the insulin receptor substrate-1 (IRS1) investigated in epididymal and visceral adipose tissues of ob/ob, wild-type and glucosamine challenged mice by immunoprecipitation. Results We found that reduced O-GlcNAc levels in visceral and epididymal adipose tissues of obese and insulin-resistant ob/ob mice, although interestingly we observed that increased O-GlcNAc modification in glucosamine challenged wild-type mice resulted in insulin resistance and ER stress. Furthermore, we demonstrated that the IRS1 was modified with O-GlcNAc in visceral and epididymal adipose tissues in both ob/ob mice and glucosamine-injected mice, and was compatible with the serine phosphorylation of this modification. Conclusion Our results suggest that O-GlcNAcylation of proteins is a crucial factor for intracellular trafficking regulates insulin receptor signaling and UPR depending on the cellular state of insulin resistance.

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