Interaction of uteroplacental insufficiency and postnatal Western diet on the hepatic transcriptome in young adult female and male Guinea pigs

Epidemiological and animal studies highlight an adverse in utero environment, often associated with low birth weight (LBW) and intrauterine growth restriction (IUGR), and postnatal intake of energy-dense foods, interact in the development of nonalcoholic fatty liver disease (NAFLD) in offspring. While these associations are emerging, understanding the specific contributions of LBW/IUGR and energy-dense food such as Western diet (WD) to the hepatic transcriptome and development of NAFLD is lacking. This study used a guinea pig model of uteroplacental insufficiency (UPI) to induce LBW/IUGR. It applied microarray-based expression profiling with epigenetic marker analysis to explore mechanisms by which UPI may predisposes WD-fed young adult offspring to NAFLD. At postnatal day 150, male and female WD offspring exhibited lean NAFLD, regardless of birth weight. WD consumption led to downregulation of the steroid biosynthesis, upregulation of ECM-receptor interaction, cell cycle, lysosome, and AGE-RAGE signaling pathways in both sexes. Additionally, genes in the p53 signaling pathway were upregulated in WD males, while the PPAR signaling pathway was upregulated in WD females, independent of birth weight. MicroRNA (miR)-target gene interactions and RTqPCR analyses revealed that miR-26b-5p in males and miR-29-3p in females were linked to these pathway changes. The combination of LBW and WD caused changes in hepatic adrenergic and calcium signaling in females and NF-kappa beta signaling in males. This study shows that although LBW and WD each uniquely and jointly affect the hepatic transcriptome, WD alone appears to be a significant environment underlying NAFLD in young adult female and male guinea pigs.