New Insights on the Regulation of the Insulin-Degrading Enzyme: Role of microRNAs and RBPs

Abstract

The evident implication of the insulin-degrading enzyme (IDE) in Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM), among its capacity to degrade insulin and amyloid-β peptide (Aβ), suggests that IDE could be an essential link in the relation between hyperinsulinemia, insulin resistance and AD. However, little is known about the cellular and molecular regulation of IDE expression, and even less has been explored regarding the post-transcriptional regulation of IDE, although it represents a great molecular target of interest for therapeutic treatments. We recently described that miR-7, a novel candidate for linking AD and T2DM at the molecular level, regulates IDE and other key genes in both pathologies, including some key genes involved in the insulin signaling pathway. Here, we explored whether other miRNAs as well as other post-transcriptional regulators, such as RNA binding proteins (RBP), could potentially participate in the regulation of IDE expression in vitro. Our data showed that in addition to miR-7, miR-125, miR-490 and miR-199 regulate IDE expression at the post-transcriptional level. Moreover, we also found that IDE contains multiple potential binding sites for several RBPs, and a narrow-down prediction analysis led us to speculate on a novel regulation of IDE by RALY and HuD. Taken together, these results demonstrate the novel players controlling IDE expression that could represent potential therapeutical targets to treat several metabolic diseases with a high impact on human health, including AD and T2DM.

Association between polymorphism rs2421943 of the insulin‐degrading enzyme and schizophrenia: Preliminary report

“…This reduction in IDE enzymatic activity would lead to increased levels of insulin interacting with brain regions involved in cognitive function 46,47 . In addition, recent in vitro studies have demonstrated the role of miRNAs and RNA‐binding proteins in IDE regulation 48 …”

“… 46 , 47 In addition, recent in vitro studies have demonstrated the role of miRNAs and RNA‐binding proteins in IDE regulation. 48 …”

Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aβ Metabolism

“…It has been also demonstrated that overnutrition-related signals upregulate the expression of Bace1 [39]. Accordingly, IDE can be finely modulated by metabolic stimuli, and it has been proposed as a key molecular link between AD and insulin resistance [40,41]. It has been demonstrated that HFD may induce hippocampal insulin resistance by altering the activation of insulin receptor downstream effectors and transcription factors [27].…”

Female‐to‐male differential transcription patterns of miRNA‐mRNA networks in the livers of dioxin‐exposed mice

“…These small non-coding RNA molecules bind by complementarity to the 3 0 -UTR of target mRNAs, regulating therefore their expression at posttranscriptional and translational levels and subsequently controlling diverse biological processes, for example, embryonic development, fat storage, insulin secretion, drug metabolism, apoptosis, cell growth and tumorigenesis. [82][83][84][85][86][87] The involvement of liver miRNAs in the regulation of genes expression as a response to dioxin exposure was previous investigated over a restricted scale. [88][89][90] Thus, the current study was conducted to present a wider overview on the transcriptional pattern of miRNAs in the mouse liver after exposure to TCDD to determine the potential regulatory effects these miRNAs on the target mRNAs.…”

“…MicroRNAs (miRNAs) gained a considerable attention as effective and determinant suppressors for the expression of target mRNAs. These small non‐coding RNA molecules bind by complementarity to the 3′‐UTR of target mRNAs, regulating therefore their expression at posttranscriptional and translational levels and subsequently controlling diverse biological processes, for example, embryonic development, fat storage, insulin secretion, drug metabolism, apoptosis, cell growth and tumorigenesis 82–87 …”