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Signal Transduction

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

  1. Hao Wang1,
  2. Yongyan Song2,
  3. Yuxin Wu1,
  4. Virender Kumar3,
  5. Ram I. Mahato3 and
  6. Qiaozhu Su1,2⇑
  1. 1Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, U.K.
  2. 2Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE
  3. 3Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE
  1. Corresponding author: Qiaozhu Su, q.su{at}qub.ac.uk
  1. H.W., Y.S., and Y.W. contributed equally to the work.

Diabetes 2021 Mar; 70(3): 710-719. https://doi.org/10.2337/db20-0181
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Abstract

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

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.13491342.

  • Received February 21, 2020.
  • Accepted December 24, 2020.
  • © 2021 by the American Diabetes Association
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Activation of dsRNA-Dependent Protein Kinase R by miR-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance
Hao Wang, Yongyan Song, Yuxin Wu, Virender Kumar, Ram I. Mahato, Qiaozhu Su
Diabetes Mar 2021, 70 (3) 710-719; DOI: 10.2337/db20-0181

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Activation of dsRNA-Dependent Protein Kinase R by miR-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance
Hao Wang, Yongyan Song, Yuxin Wu, Virender Kumar, Ram I. Mahato, Qiaozhu Su
Diabetes Mar 2021, 70 (3) 710-719; DOI: 10.2337/db20-0181
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