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

EBioMedicine
Jèssica LatorreJosé M Fernández-Real

Abstract

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). 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. 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 meta...Continue Reading

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Citations

Aug 29, 2020·The Journal of Pharmacy and Pharmacology·Thamires Barros TavaresCristiane Aguiar da Costa
Sep 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Bruna B BrandãoMarcelo A Mori
Jul 11, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Nahid AlimoradiReihaneh Fatehi

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Datasets Mentioned

BETA
GSE145039

Methods Mentioned

BETA
transfection
biopsy
PCR
Protein Assay
ELISA
Assay
Low Density Arrays
transfections
PCA
biopsies

Software Mentioned

FIJI J
SPSS
QuantStudio TM Real - Time PCR
DAVID
DIANA
miRpath
Image J
TargetScan
GraphPad Prism
QuantStudio

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