Maternal Nutrient Restriction Disrupts Gene Expression and Metabolites Associated with Urea Cycle, Steroid Synthesis, Glucose Homeostasis, and Glucuronidation in Fetal Calf Liver.

Susumu Muroya,Mitsue Sano,Sanggun Roh,Ichiro Oshima,Takafumi Gotoh,Kounosuke Otomaru,Yi Zhang,Koichi Ojima,Kazunaga Oshima

doi:10.3390/metabo12030203

Abstract

This study aimed to understand the mechanisms underlying the effects of maternal undernutrition (MUN) on liver growth and metabolism in Japanese Black fetal calves (8.5 months in utero) using an approach that integrates metabolomics and transcriptomics. Dams were fed 60% (low-nutrition; LN) or 120% (high-nutrition; HN) of their overall nutritional requirements during gestation. We found that MUN markedly decreased the body and liver weights of the fetuses; metabolomic analysis revealed that aspartate, glycerol, alanine, gluconate 6-phosphate, and ophthalmate levels were decreased, whereas UDP-glucose, UDP-glucuronate, octanoate, and 2-hydroxybutyrate levels were decreased in the LN fetal liver (p ≤ 0.05). According to metabolite set enrichment analysis, the highly different metabolites were associated with metabolisms including the arginine and proline metabolism, nucleotide and sugar metabolism, propanoate metabolism, glutamate metabolism, porphyrin metabolism, and urea cycle. Transcriptomic and qPCR analyses revealed that MUN upregulated QRFPR and downregulated genes associated with the glucose homeostasis (G6PC, PCK1, DPP4), ketogenesis (HMGCS2), glucuronidation (UGT1A1, UGT1A6, UGT2A1), lipid metabolism (ANGPTL4, APOA5, FADS2), cholesterol and steroid homeostasis (FDPS, HSD11B1, HSD17B6), and urea cycle (CPS1, ASS1, ASL, ARG2). These metabolic pathways were extracted as relevant terms in subsequent gene ontology/pathway analyses. Collectively, these results indicate that the citrate cycle was maintained at the expense of activities of the energy metabolism, glucuronidation, steroid hormone homeostasis, and urea cycle in the liver of MUN fetuses.

Highlights

Maternal undernutrition (MUN) during gestation in mammals causes retardation of fetal development, which is a typical fetal growth restriction (FGR; known as intrauterine growth restriction) [1]
maternal undernutrition (MUN) markedly decreased the mass of liver in fetuses of the low nutrient (LN) group [22]
The expression of ACOX2, a gene involved in primary bile acid synthesis, was suppressed. These results indicate that MUN resulted in the suppression of steroid and primary bile acid synthesis in fetal liver metabolism, as indicated by metabolite set enrichment analysis (MSEA) and gene ontology (GO) analysis (Tables 3 and 4)

Summary

Introduction

Maternal undernutrition (MUN) during gestation in mammals causes retardation of fetal development, which is a typical fetal growth restriction (FGR; known as intrauterine growth restriction) [1]. Even if there is no phenotypic impact, gene expression and metabolites in fetal organs are altered due to physiological adaptations in response to low nutrient levels, which are linked to epigenetic changes, including DNA methylation in mise and rats [4]. This epigenetic mechanism is thought to promote the development and growth of MUN fetal organs to establish a thrifty constitution in nutrient-restricted dams during gestation in mammals [5]. Farm animals such as sheep are good models to investigate the impact of MUN on human fetuses and offspring due to the high similarity to human placental and fetal development compared to rodents [7], especially in terms of the developmental origin of metabolic disease in adulthood

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