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.

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

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.

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.

Sign in / Sign up

Export Citation Format

Share Document