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. 2021 Jan 7;70(3):710–719. doi: 10.2337/db20-0181

Figure 7.

Figure 7

miR-378a targets the 3′-UTR of PPARα mRNA and activates the dsRNA-dependent PKR in metabolic inflammation. Metabolic inflammatory inducers, such as a high-fructose diet and inflammatory cytokine TNF-α, induce expression of miR-378a, which targets multiple miRNA response elements within the 3′-UTR of PPARα mRNA and induces mitochondrial and ER stress. Upregulated miR-378a further directly binds to the dsRNA-binding domains in PKR and activates the kinase to sustain the metabolic inflammation and induces IRS-1-pS307, which blunts hepatic insulin signaling. Genetic depletion of miR-378a (miR-378a-KO) or treatment with an anti-miR-378a oligonucleotide that counterbalances miR-378a expression can ameliorate inflammatory stress and improve insulin resistance. dsRBM, double-stranded RNA-binding motif; KD, kinase domain; Pi, phosphorylation.