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

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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Abstract 552: Aberrant Expression of MicroRNA-378a Induces Hepatic Insulin Resistance via Activation of ER Stress and the dsRNA Activated Protein Kinase PKR

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.552 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Xiao Cheng ◽

Yongyan Song ◽

Qiaozhu Su

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Er Stress ◽

Target Genes ◽

Rna Binding ◽

Mrna Level ◽

Hepatic Insulin Resistance ◽

Stress Signaling ◽

Aberrant Expression ◽

Mitochondrial Fatty Acid

microRNAs(miRNAs) are noncoding RNAs with a length of 19 to 25 nt that are involved in posttranscriptional gene regulation by binding to the 3’-untranslated regions (3’-UTR) of target mRNA and impacting diverse cellular processes, including cell differentiation, energy metabolism and chronic inflammation. MicroRNA-378a (miR-378a) has been reported to be involved in adipose tissue browning and cancer development. However, its role in cellular stress signaling and hepatic insulin resistance has not yet been investigated. Here we reported that expression of hepatic miR-378a was upregulated by metabolic inflammatory inducers, such as high fructose feeding, bacterial lipopolysaccharide (LPS) and inflammatory cytokine TNFα. The elevated miR-378a subsequently targeted the 3’-UTR of PPARα which compromised mitochondrial fatty acid β-oxidation and induced mitochondrial and ER stress. miR-378a was further found to directly interacted with the dsRNA binding motifs within the dsRNA activated protein kinase PKR and activated the kinase to sustain the inflammatory stress and blunt the insulin signaling in hepatocytes. Genetic depletion of miR-378a rescued hepatocytes from mitochondrial and ER stress, systemic inflammation and insulin resistance induced by fructose and LPS. Conclusion: This study, for the first time, demonstrates that miR-378a is involved in mediating the metabolic inflammatory response in the onset of insulin resistance. This study further unveils a novel finding that miR-378a is capable of directly interacting with and activating a protein kinase PKR to sustain the stress signaling between mitochondria and ER. This discovery greatly broadens the physiological function of miR-378a by demonstrating that, in addition to regulate its target genes on the mRNA level, miRNA-378a is able to interact with RNA binding protein(s) and exerts its regulatory effect directly on the protein levels. Results from this study may provide rationale for using miR-378a as a pharmaceutical target in the treatment of insulin resistance.

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Activation of Hepatic Inflammatory Pathways by Catecholamines Is Associated With Hepatic Insulin Resistance in Male Ischemic Stroke Rats

Endocrinology ◽

10.1210/en.2013-1593 ◽

2014 ◽

Vol 155 (4) ◽

pp. 1235-1246 ◽

Cited By ~ 25

Author(s):

Ya-Yu Wang ◽

Shih-Yi Lin ◽

Yu-Han Chuang ◽

Wayne Huey-Herng Sheu ◽

Kwong-Chung Tung ◽

...

Keyword(s):

Insulin Resistance ◽

Ischemic Stroke ◽

Er Stress ◽

Acute Stroke ◽

Acute Ischemic Stroke ◽

Resistance Index ◽

Serine Phosphorylation ◽

Hepatic Insulin Resistance ◽

Insulin Resistance Index ◽

Tnf Α

Patients who experience acute ischemic stroke may develop hyperglycemia, even in the absence of diabetes. In the current study we determined the effects of acute stroke on hepatic insulin signaling, TNF-α expression, endoplasmic reticulum (ER) stress, the activities of c-Jun N-terminal kinase (JNK), inhibitor κB kinase β (IKK-β), and nuclear factor-κB (NF-κB) pathways. Rats with cerebral ischemia developed higher blood glucose, and insulin levels, and insulin resistance index, as well as hepatic gluconeogenic enzyme expression compared with the sham-treated group. The hepatic TNF-α mRNA and protein levels were elevated in stroke rats in association with increased ER stress, phosphorylation of JNK1/2 and IKK-β proteins, IκB/NF-κB signaling, and phosphorylation of insulin receptor-1 (IRS-1) at serine residue. The basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and AKT proteins was reduced. In addition, acute stroke increased circulating catecholamines in association with hepatic adrenergic signaling activation. After administration of a nonselective β-adrenergic receptor blocker (propranolol) before induction of cerebral ischemic injury, hepatic adrenergic transduction, TNF-α expression, ER stress, and the activation of the JNK1/2, IKK-β, and NF-κB pathways, and serine phosphorylation of IRS-1 were all attenuated. In contrast, the phosphorylated IRS-1 at tyrosine site and AKT levels were partially restored with improved poststroke hyperglycemia and insulin resistance index. These results suggest that acute ischemic stroke can activate proinflammatory pathways in the liver by the catecholamines and is associated with the development of hepatic insulin resistance.

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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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Activation of dsRNA-Dependent Protein Kinase R by MicroRNA-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance

10.2337/figshare.13491342.v1 ◽

2021 ◽

Author(s):

Hao Wang ◽

Yongyan Song ◽

Yuxin Wu ◽

Virender Kumar ◽

Ram I Mahato ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Er Stress ◽

Rna Binding ◽

Hepatic Insulin Resistance ◽

Protein Kinase R ◽

Dependent Protein Kinase ◽

Metabolic Inflammation ◽

Mitochondrial Fatty Acid ◽

Dependent Protein

<a>MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here we reported that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine TNF</a>a. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated which, in turn, targeted the 3’-UTR of PPARa mRNA, impaired mitochondrial fatty acid b-oxidation and induced mitochondrial and ER stress. More importantly, the upregulated miR-378a can directly bind to and activate the dsRNA-dependent protein kinase R (PKR) to sustain the metabolic stress. <i>In vivo</i>, genetic depletion of miR-378a prevented PKR activation, ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPARa activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in the fructose-fed mice. <i>Conclusion: </i>Our study delineated a novel mechanism of miRNA-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPARa) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding protein(s) (e.g., PKR) is biologically significant as it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes.

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Effect of BI-1 on insulin resistance through regulation of CYP2E1

Scientific Reports ◽

10.1038/srep32229 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 7

Author(s):

Geum-Hwa Lee ◽

Kyoung-Jin Oh ◽

Hyung-Ryong Kim ◽

Hye-Sook Han ◽

Hwa-Young Lee ◽

...

Keyword(s):

Insulin Resistance ◽

Er Stress ◽

Insulin Signaling ◽

High Fat Diet ◽

Stable Expression ◽

Hepatic Insulin Resistance ◽

Ros Production ◽

High Fat ◽

Knock Out ◽

Knock Out Mice

Abstract Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production.

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4-Phenylbutyric acid improves free fatty acid-induced hepatic insulin resistance in vivo

Endocrine Connections ◽

10.1530/ec-21-0248 ◽

2021 ◽

Vol 10 (8) ◽

pp. 861-872

Author(s):

Sandra Pereira ◽

Jessy Moore ◽

Jia-Xu Li ◽

Wen Qin Yu ◽

Husam Ghanim ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Er Stress ◽

Mitogen Activated Protein Kinase ◽

Hepatic Insulin Resistance ◽

Initiation Factor ◽

Fibroblast Growth Factor 21 ◽

Chemical Chaperone ◽

Fetuin A ◽

Phenylbutyric Acid

Plasma free fatty acids (FFAs) are elevated in obesity and can induce insulin resistance via endoplasmic reticulum (ER) stress. However, it is unknown whether hepatic insulin resistance caused by the elevation of plasma FFAs is alleviated by chemical chaperones. Rats received one of the following i.v. treatments for 48 h: saline, intralipid plus heparin (IH), IH plus the chemical chaperone 4-phenylbutyric acid (PBA), or PBA alone and a hyperinsulinemic-euglycemic clamp was performed during the last 2 h. PBA co-infusion normalized IH-induced peripheral insulin resistance, similar to our previous findings with an antioxidant and an IκBα kinase β (IKKβ) inhibitor. Different from our previous results with the antioxidant and IKKβ inhibitor, PBA also improved IH-induced hepatic insulin resistance in parallel with activation of Akt. Unexpectedly, IH did not induce markers of ER stress in the liver, but PBA prevented IH-induced elevation of phosphorylated eukaryotic initiation factor-2α protein in adipose tissue. PBA tended to decrease circulating fetuin-A and significantly increased circulating fibroblast growth factor 21 (FGF21) without affecting markers of activation of hepatic protein kinase C-δ or p38 mitogen-activated protein kinase that we have previously involved in hepatic insulin resistance in this model. In conclusion: (i) PBA prevented hepatic insulin resistance caused by prolonged plasma FFA elevation without affecting hepatic ER stress markers; (ii) the PBA effect is likely due to increased FGF21 and/or decreased fetuin-A, which directly signal to upregulate Akt activation.

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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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