Identification of two microRNA nodes as potential cooperative modulators of liver metabolism.

AIM: Hepatic insulin resistance is a hallmark of type 2 diabetes and non-alcoholic fatty liver disease. Dysregulation of microRNA (miRNA) expression in insulin-resistant livers might coordinate impaired hepatic metabolic function. Here, we aimed to discover miRNAs and their downstream targets involved in hepatic insulin resistance. METHODS: We determined miRNA expression profiles by small RNA sequencing of two mouse models of impaired hepatic insulin action: high-fat diet-induced obesity and liver-specific insulin receptor knockout. Conversely, we assessed the hepatic miRNA expression profile after treatment with the antidiabetic hormone, fibroblast growth factor 21 (FGF21). Ontology analysis of predicted miRNA gene targets was performed to identify regulated gene pathways. Target enrichment analysis and miRNA mimic overexpression in vitro were used to identify unified protein targets of nodes of regulated miRNAs. RESULTS: We identified an array of miRNA species regulated by impaired liver insulin action or after fibroblast growth factor 21 treatment. Ontology analysis of predicted miRNA gene targets identified pathways controlling hepatic energy metabolism and insulin sensitivity. We identified a node of two miRNAs downregulated in the livers of liver-specific insulin receptor knockout mice, miR-883b and miR-205, which positively regulate the expression of transcription factor zinc finger E-box-binding homeobox 1 (ZBED1). We found another node of two miRNAs upregulated in the livers of fibroblast growth factor 21-treated mice, miR-155-3p and miR-1968-5p, which canonically downregulates the caveola component, polymerase I and transcript release factor (PTRF), a gene previously implicated in hepatic energy metabolism. CONCLUSIONS: This study identifies two nodes of coregulated miRNAs that might coordinately control hepatic energy metabolism in states of insulin resistance.

MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from simple hepatic steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which may progress to cirrhosis and liver cancer. NAFLD is rapidly becoming a global health challenge, and there is a need for improved diagnostic- and prognostic tools and for effective pharmacotherapies to treat NASH. The molecular mechanisms of NAFLD development and progression remain incompletely understood, though ample evidence supports a role of microRNAs (miRNAs) - small non-coding RNAs regulating gene expression - in the progression of metabolic liver disease. SCOPE OF REVIEW: In this review, we summarise the currently available liver miRNA profiling studies in people with various stages of NAFLD. We further describe the mechanistic role of three of the most extensively studied miRNA species, miR-34a, miR-122 and miR-21, and highlight selected findings on novel NAFLD-linked miRNAs. We also examine the literature on exosomal microRNAs (exomiRs) as inter-hepatocellular or -organ messengers in NAFLD. Furthermore, we address the status for utilizing circulating NAFLD-associated miRNAs as minimally invasive tools for disease diagnosis, staging and prognosis as well as their potential use as NASH pharmacotherapeutic targets. Finally, we reflect on future directions for research in the miRNA field. MAJOR CONCLUSIONS: NAFLD is associated with changes in hepatic miRNA expression patterns at early, intermediate and late stages, and specific miRNA species appear to be involved in steatosis development and NAFL progression to NASH and cirrhosis. These miRNAs act either within or between hepatocytes and other liver cell types such as hepatic stellate cells and Kupffer cells or as circulating inter-organ messengers carrying signals between the liver and extra-hepatic metabolic tissues, including the adipose tissues and the cardiovascular system. Among circulating miRNAs linked to NAFLD, miR-34a, miR-122 and miR-192 are the best candidates as biomarkers for NAFLD diagnosis and staging. To date, no miRNA-targeting pharmacotherapy has been approved for the treatment of NASH, and no such therapy is currently under clinical development. Further research should be conducted to translate the contribution of miRNAs in NAFLD into innovative therapeutic strategies.

Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health.

OBJECTIVES: Regular physical exercise improves health by reducing the risk of a plethora of chronic disorders. We hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle and that this remodeling contributes to the beneficial effects of exercise on human health. METHODS AND RESULTS: By studying changes in histone modifications, we mapped the genome-wide positions and activities of enhancers in skeletal muscle biopsies collected from young sedentary men before and after 6 weeks of endurance exercise. We identified extensive remodeling of enhancer activities after exercise training, with a large subset of the remodeled enhancers located in the proximity of genes transcriptionally regulated after exercise. By overlapping the position of enhancers with genetic variants, we identified an enrichment of disease-associated genetic variants within the exercise-remodeled enhancers. CONCLUSION: Our data provide evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans.