MicroRNA-378 in metabolic inflammatory stress and hepatic insulin resistance
Problem Statement: MicroRNAs (miRNAs) are non-coding RNAs with a length of 19-25 nt that are involved in post-transcriptional gene regulation by binding to the 3'-untranslated regions (3'-UTR) of targeted and impacting mRNA in various cellular processes, including cellular differentiation, energy metabolism, and chronic inflammation. MicroRNA-378a (miR-378a) has been reported to regulate adipose tissue blackening and the development of cancer. However, its role in signaling cellular stress and hepatic insulin resistance has not yet been investigated. Findings: We report here that hepatic miR378a expression was regulated by inflammatory metabolic inducers, such as high-fructose diet, bacterial lipopolysaccharide (LPS), and inflammatory cytokine TNFα.
Subsequently, the elevated miR378a was directed to the 3'-UTR of PPARα that compromised β oxidation of mitochondrial fatty acids and induced mitochondrial stress and ER. Furthermore, miR-378a was found to interact directly with dsRNA binding motifs within the dsRNA-activated protein kinase PKR and activated the kinase to maintain inflammatory stress and mitigate insulin signaling in the liver. Genetic depletion of miR-378a rescued hepatocytes from mitochondrial stress and ER,
systemic inflammation and insulin resistance induced by fructose and LPS. Conclusion and importance: This study, for the first time, demonstrates that miR-378a is a mediator in metabolic inflammatory stress and contributes to the initiation of insulin resistance. It also reveals that a certain miRNA is capable of directly interacting and activating the PKR protein kinase to maintain stress signaling between mitochondria and the emergency room. This discovery greatly expands the physiological function of miRNAs by demonstrating that, in addition to target genes at the mRNA level, miRNAs can interact with RNA-binding proteins and directly exert their regulatory effect on protein levels.
The results of this study may provide a rationale for using miR-378a as a pharmaceutical target in the prevention and treatment of insulin resistance and related metabolic syndrome. The pathogenesis of insulin resistance involves the expression and function of dysregulated genes in multiple cell types, including endothelial cells (EC). Post-transcriptional mechanisms such as microRNA-mediated gene expression regulation could affect insulin action by modulating EC function. Our data underscores the importance of adipose tissue EC function in controlling the development of insulin resistance.
When hepatocytes are severely damaged, a variety of signaling pathways will be triggered by inflammatory factors and cytokines that are involved in the process of liver fibrosis. The microRNA family (miRNA) consists of several miRNAs that have the potential for synergistic regulation of these signaling pathways. However, it is poor to understand the roles of the miRNA family as a whole in liver fibrosis. Growing studies have suggested that several miRNA families are related to hepatic stellate cell activation and liver fibrosis through cooperative regulation of certain signaling pathways.
During the liver fibrosis process, the miR-29 family mainly induces cellular apoptosis by modulating the phosphatidylinositol 3-kinase / AKT signaling pathway and regulating the accumulation of extracellular matrix. The miR-34 family promotes the progression of liver fibrosis by inducing activation of liver stellate cells, while the miR-378 family suppresses the process in a Glis-dependent manner. The miR-15 family mainly promotes cell proliferation and induces apoptosis. The miR-199 family and the miR-200 family are responsible for the deposition of the extracellular matrix and the release of pro-fibrotic cytokines. These miRNA family members perform pro-fibrotic or antifibrotic functions by targeting genes collectively or respectively that participate in signaling pathways related to liver fibrosis and activation of liver stellate cells. Therefore, a good understanding of the molecular mechanisms that are based on miRNA families may provide new ideas for targeted molecular therapy of liver fibrosis in the future.