Placental restriction co-ordinately alters hepatic expression of microRNAs and targets related to non alcoholic fatty liver disease, in adult male sheep
H. Harryanto, M. De Blasio, P. Grant, K. Gatford & J. Owens
Placental restriction (PR) of fetal growth impairs insulin action and metabolic control in postnatal life. MicroRNAs (miRNAs) are important post-transcriptional regulators, down regulating mRNA abundance or translation. We therefore determined if PR in the sheep alters miR expression in liver, skeletal muscle and adipose tissue of adult offspring and if this associates with altered abundance of their predicted molecular targets.
PR was induced by pre-pregnancy removal of most uterine implantation sites. Control (8 male, 8 female) and PR (6 male, 8 female) sheep had insulin sensitivity and metabolism measured at 12 months, then tissues collected for RNA extraction. MiRNA expression was measured by Exiqon miRarray (v8.1) (R, with adjustment for multiple comparisons) and RTPCR, as was expression of predicted targets (identified by algorithms, then networks and pathways by IPA). Effects of PR and sex were assessed by ANOVA, associations by Pearsons correlation, with statistical significance at P<0.05.
PR mostly increased microRNA expression in insulin sensitive tissues of adult sheep. In males, PR increased hepatic expression of eight miRNAs by ~1.5-3.5-fold, with differential expression of four independently confirmed (miR 1, 21, 142-3p and 144), each predicted to target molecules involved in insulin signalling, metabolism and hepatic disease. The latter include p85α, Pparα, Igf1, Foxo3 and Acox1, all exhibiting reduced hepatic expression (~ 2.3-4.0 fold) following PR in males, with the abundance of miR-1, 142-3p and -144 correlating negatively with Acox1 expression.
These findings show for the first time that PR co-ordinately alters hepatic expression of miRs and predicted targets related to non-alcoholic fatty liver disease (NAFLD), in adult male offspring. Reduced hepatic expression of Pparα (regulates lipid catabolism), and Acox1 (peroxisomal fatty acid β-oxidation) characterise or promote development of NAFLD, increasingly common following fetal growth restriction in humans, and microRNAs may partly mediate this prenatal programming of NAFLD.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.