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

Ragunath Singaravelu,Daniel M Jones,Curtis Quan,Prashanth Srinivasan,Tyler A Shaw,Rodney K Lyn,Megan H Powdrill,Roxana Filip,Rodney S Russell,John P Pezacki,Rhea C Alonzi

doi:10.1038/s41598-017-18529-x

Ragunath Singaravelu, Daniel M Jones + Show 9 more

Open Access

https://doi.org/10.1038/s41598-017-18529-x

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Abstract

MicroRNAs (miRNAs) have emerged as critical regulators of cellular metabolism. To characterise miRNAs crucial to the maintenance of hepatic lipid homeostasis, we examined the overlap between the miRNA signature associated with inhibition of peroxisome proliferator activated receptor-α (PPAR-α) signaling, a pathway regulating fatty acid metabolism, and the miRNA profile associated with 25-hydroxycholesterol treatment, an oxysterol regulator of sterol regulatory element binding protein (SREBP) and liver X receptor (LXR) signaling. Using this strategy, we identified microRNA-7 (miR-7) as a PPAR-α regulated miRNA, which activates SREBP signaling and promotes hepatocellular lipid accumulation. This is mediated, in part, by suppression of the negative regulator of SREBP signaling: ERLIN2. miR-7 also regulates genes associated with PPAR signaling and sterol metabolism, including liver X receptor β (LXR-β), a transcriptional regulator of sterol synthesis, efflux, and excretion. Collectively, our findings highlight miR-7 as a novel mediator of cross-talk between PPAR, SREBP, and LXR signaling pathways in the liver.

Highlights

The human liver plays a central role in systemic metabolism[1]
peroxisome proliferator activated receptors (PPARs) and liver X receptor (LXR) compete for retinoid X receptor (RXR) binding to activate their respective signaling pathways, and peroxisome proliferator activated receptor-α (PPAR-α) overexpression interferes with LXR-mediated activation of SREBP1 expression[7,8]
Our findings suggest a novel role for a PPAR-α regulated miRNA, miRNA-7, in the regulation of sterol regulatory element binding protein (SREBP) signaling. miR-7 stimulates the activity of SREBPs, master regulators of lipid biosynthesis

Summary

Introduction

The human liver plays a central role in systemic metabolism[1]. Proper regulation of gene networks in the liver is integral to the maintenance of energy homeostasis[1]. We sought to characterise miRNAs regulating PPAR, LXR, and SREBP signaling to gain insight into the molecular mechanisms of cross-talk between these metabolic pathways. Our work highlights miR-7 as a novel mediator of cross-talk between the PPAR-α, LXR-β, and SREBP signaling pathways.

Results

Conclusion