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

Diabetes ◽  
2021 ◽  
pp. db200181
Author(s):  
Hao Wang ◽  
Yongyan Song ◽  
Yuxin Wu ◽  
Virender Kumar ◽  
Ram I Mahato ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Protein Kinase R ◽  
Dependent Protein Kinase ◽  
Metabolic Inflammation ◽  
Dependent Protein

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

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.

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

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.

Alterations in cardiac contractile performance and sarcoplasmic reticulum function in sucrose-fed rats is associated with insulin resistance

2006 ◽  
Vol 291 (4) ◽  
pp. C772-C780 ◽  
Author(s):  
Zainisha Vasanji ◽  
Elliott J. F. Cantor ◽  
Danijel Juric ◽  
Mellissa Moyen ◽  
Thomas Netticadan
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Sarcoplasmic Reticulum ◽  
Whole Body ◽  
Dependent Protein Kinase ◽  
Cardiac Contractile ◽  
Type 2 Dm ◽  
Dependent Protein ◽  
Contractile Performance

Diabetes mellitus (DM) causes the development of a specific cardiomyopathy that results from the metabolic derangements present in DM and manifests as cardiac contractile dysfunction. Although myocardial dysfunction in Type 1 DM has been associated with defects in the function and regulation of the sarcoplasmic reticulum (SR), very little is known about SR function in Type 2 DM. Accordingly, this study examined whether abnormalities in cardiac contractile performance and SR function occur in the prestage of Type 2 DM (i.e., during insulin resistance). Sucrose feeding was used to induce whole body insulin resistance, whereas cardiac contractile performance was assessed by echocardiography and SR function was measured by SR calcium (Ca2+) uptake. Sucrose-fed rats exhibited hyperinsulinemia, hyperglycemia, and hyperlipidemia relative to control rats. Serial echocardiographic assessments in the sucrose-fed rats revealed early abnormalities in diastolic function followed by late systolic dysfunction and concurrent alterations in myocardial structure. The hearts of the 10-wk sucrose-fed rats showed depressed SR function demonstrated by a significant reduction in SR Ca2+ uptake. The decline in SR Ca2+ uptake was associated with a significant decrease in the cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of phospholamban. The results show that abnormalities in cardiac contractile performance and SR function occur at an insulin-resistant stage before the manifestation of overt Type 2 DM.

Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise

2008 ◽  
Vol 294 (3) ◽  
pp. E607-E614 ◽  
Author(s):  
Elena De Filippis ◽  
Guy Alvarez ◽  
Rachele Berria ◽  
Kenneth Cusi ◽  
Sarah Everman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Protein Kinase ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Gene ◽  
Mitochondrial Genes ◽  
Protein Abundance ◽  
Dependent Protein Kinase ◽  
Insulin Resistant ◽  
Dependent Protein

Mitochondrial dysfunction, associated with insulin resistance, is characterized by low expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and nuclear-encoded mitochondrial genes. This deficit could be due to decreased physical activity or a decreased response of gene expression to exercise. The objective of this study was to investigate whether a bout of exercise induces the same increase in nuclear-encoded mitochondrial gene expression in insulin-sensitive and insulin-resistant subjects matched for exercise capacity. Seven lean and nine obese subjects took part. Insulin sensitivity was assessed by an 80 mU·m−2·min−1 euglycemic clamp. Subjects were matched for aerobic capacity and underwent a single bout of exercise at 70 and 90% of maximum heart rate with muscle biopsies at 30 and 300 min postexercise. Quantitative RT-PCR and immunoblot analyses were used to determine the effect of exercise on gene expression and protein abundance and phosphorylation. In the postexercise period, lean subjects immediately increased PGC-1α mRNA level (reaching an eightfold increase by 300 min postexercise) and protein abundance and AMP-dependent protein kinase phosphorylation. Activation of PGC-1α was followed by increase of nuclear respiratory factor-1 and cytochrome c oxidase (subunit VIc). However, in insulin-resistant subjects, there was a delayed and reduced response in PGC-1α mRNA and protein, and phosphorylation of AMP-dependent protein kinase was transient. None of the genes downstream of PGC-1α was increased after exercise in insulin resistance. Insulin-resistant subjects have a reduced response of nuclear-encoded mitochondrial genes to exercise, and this could contribute to the origin and maintenance of mitochondrial dysfunction.

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