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Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes

Latorre, Jèssica, Ortega, Francisco J., Liñares-Pose, Laura, Moreno-Navarrete, José M., Lluch, Aina, Comas, Ferran, Oliveras-Cañellas, Núria, Ricart, Wifredo, Höring, Marcus, Zhou, You, Liebisch, Gerhard, Nidhina Haridas, P.A., Olkkonen, Vesa M., López, Miguel and Fernández-Real, José M. 2020. Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes. EBioMedicine 53 , 102697. 10.1016/j.ebiom.2020.102697

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Abstract

Background While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled β-oxidation, redirecting FA metabolism from energy storage to expenditure. Interpretation Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: Elsevier
ISSN: 2352-3964
Date of First Compliant Deposit: 12 March 2020
Date of Acceptance: 16 February 2020
Last Modified: 13 Mar 2020 10:00
URI: http://orca.cf.ac.uk/id/eprint/130349

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