1872-P: Hepatic miR-582-5p Is Programmed by Maternal Diet-Induced Obesity in Male Mice and Contributes to Nonalcoholic Fatty Liver Disease

Abstract

Obesity during pregnancy is associated with increased risk of nonalcoholic fatty liver disease (NAFLD) in the offspring; however, the underlying molecular mechanisms remain largely unknown. The aim of the current study was to explore the contribution of microRNAs (miRs) as mediators of programming by maternal obesity. To achieve this, we used a mouse model of maternal-diet induced obesity where dams develop gestational diabetes and offspring demonstrate increased hepatic triglyceride content. We carried out small RNA next generation sequencing analysis of liver from twelve-week-old male offspring and identified miR-582-5p as the most dysregulated, showing a threefold increase. Binding site prediction (TargetScan 7.2) and pathway enrichment analysis (Reactome v67) suggested a number of miR-582-5p target genes related to lipid metabolism including Insulin Induced Gene 2 (INSIG2) and Translocase of Inner Mitochondrial Membrane 23 (TIMM23). Overexpression of miR-582-5p in AML12 (mouse) and HEPG2 (human) cell lines caused increased triglyceride accumulation, downregulation of INSIG2 and TIMM23, increased nuclear localization of Sterol Regulatory Element-Binding Protein 1 (SREBP-1), and overexpression of lipogenic genes. These findings suggest that overexpression of miR-582-5p induces hepatic intracellular lipid accumulation through mechanisms that involve mitochondrial malfunction and activation of de novo lipogenesis. We therefore conclude that an epigenetically programmed increase in hepatic miR-582 is a likely contributing mechanism underlying the programming of fatty liver disease in the offspring of obese gestational diabetic mothers. Disclosure L. Pantaleao: None. D. Fernandez-Twinn: None. A. Carpenter: None. E. Loche: None. L. Dearden: None. D. Duque Guimaraes: None. N.C. Penfold: None. T.J. Ashmore: None. M. Bushell: None. S. Ozanne: Advisory Panel; Self; Nestlé. Funding Brazilian National Council for the Improvement of Higher Education (BEX 10594/13-2); Brazilian National Council for Scientific and Technological Development (PDE/204416/2014-0)