MicroRNA-7 mediates cross-talk between metabolic signaling pathways in the liver

Journal article

Brain insulin resistance is a key pathological feature contributing to obesity, diabetes, and neurodegenerative disorders, including Alzheimer’s disease (AD). Besides the classic transcriptional mechanism mediated by hormones, posttranscriptional regulation has recently been shown to regulate a number of signaling pathways that could lead to metabolic diseases. Here, we show that microRNA 7 (miR-7), an abundant microRNA in the brain, targets insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and insulin-degrading enzyme (IDE), key regulators of insulin homeostatic functions in the central nervous system (CNS) and the pathology of AD. In this study, we found that insulin and liver X receptor (LXR) activators promote the expression of the intronic miR-7-1 in vitro and in vivo, along with its host heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene, encoding an RNA binding protein (RBP) that is involved in insulin action at the posttranscriptional level. Our data show that miR-7 expression is altered in the brains of diet-induced obese mice. Moreover, we found that the levels of miR-7 are also elevated in brains of AD patients; this inversely correlates with the expression of its target genes IRS-2 and IDE. Furthermore, overexpression of miR-7 increased the levels of extracellular Aβ in neuronal cells and impaired the clearance of extracellular Aβ by microglial cells. Taken together, these results represent a novel branch of insulin action through the HNRNPK–miR-7 axis and highlight the possible implication of these posttranscriptional regulators in a range of diseases underlying metabolic dysregulation in the brain, from diabetes to Alzheimer’s disease

Authors: Singaravelu, R; Quan, C; Powdrill, MH; Shaw, TA; Srinivasan, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 8
• Issue: 1
• Pages: 361-361
• Publication date: 2018-01-04
• DOI: 10.1038/s41598-017-18529-x
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Biochemistry; Receptor; microRNA; Oxysterol; Sterol; Biology; Sterol regulatory element-binding protein; Peroxisome proliferator-activated receptor; Cell biology; Transcription factor; Gene; Signal transduction; Regulator; Cholesterol; Nuclear receptor; Liver receptor homolog-1; Lipid metabolism; Liver X receptor