The role of miRNAs in the programming of offspring fatty liver by maternal diet-induced obesity

Abstract

Maternal obesity during pregnancy and/or lactation is associated with an increased risk of obesity and related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) in the offspring throughout life. Molecular mechanisms associated with maternal obesity and onset of the NAFLD in the offspring, are still not completely understood. Recently, several groups are studying the effects of dysregulated miRNAs expression on the onset of a variety of metabolic diseases. MiRNAs are short endogenous non-coding RNAs that are able to regulate the cellular protein translation and disturbances in miRNA expression profile have been related to pathological conditions such as type 2 diabetes and NAFLD. Thus, herein, we will investigate whether the effects of maternal obesity on offspring hepatic lipid accumulation are mediated via programmed changes to hepatic miRNAs and their target gene expression. For this, the present project will be based in the study a subset of hepatic miRNAs previously identified in a miRNA sequencing methodology (miRNA-Seq) that are sensitive to programming by maternal diet-induced obesity. First, the hepatic programmed miRNAs in the liver of 12 months-old offspring will be validating by qPCR, Western blotting and luciferase assay. Through a combination of literature searching combined with a search of putative miRNA target databases will define the miRNAs with the strongest potential to influence hepatic metabolic pathways via their putative target genes. Concomitantly, we will define the full spectrum of targets of miR-582-5p, using proteomic technology (pulsed- SILAC). Previous study of the researchers observed that the miR-582-5p is strongly upregulated in mice exposed to maternal obesity and an in vitro transfection of a synthetic mimic of miR-582-5p into HEPG2 cells resulted in increased lipid accumulation. In summary, with the experimental data from this study, we will be able to provide a better understanding of the mechanisms involved in the programming of NAFLD by maternal obesity, as well as present new putative targets for liver diseases therapy.