Date of Degree

9-2022

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Xinyin Jiang

Committee Members

Jorge Matias Caviglia

Anjana Saxena

Patrizia Casaccia

Jayne Raper

Caroline Johnson

Subject Categories

Animal Experimentation and Research | Biochemistry | Endocrine System Diseases | Immunopathology | Molecular, Genetic, and Biochemical Nutrition | Nutritional and Metabolic Diseases | Systems Biology

Keywords

Epigenetics, Lipidomics, Transcriptomics, Prenatal Programming, Steatohepatitis, Metabolic Disease

Abstract

Maternal obesity has led to an increase in adverse offspring developmental outcomes and a greater risk for long-term metabolic diseases. Choline, a semi-essential nutrient, can be incorporated into phosphatidylcholine (PC) as well as sphingomyelin (SM) and donate its labile methyl group for the remethylation of homocysteine after choline is oxidized to betaine. Prenatal choline insufficiency has been related to maternal obesity and metabolic diseases, such as metabolic associated fatty liver disease (MAFLD). Choline may interact with maternal obesity to influence the programming offspring.

Chapter 1 presents an introduction of choline and the various clinical outcomes associated with choline supplementation during pregnancy.

Chapter 2 presents findings of altered whole-body glucose tolerance in choline supplemented (CS) male offspring prenatally challenged by a maternal HF diet (HF+CS). Here we demonstrate benefits of choline on blood glucose control and metabolic regulation of the visceral adipose tissue.

Chapter 3 presents an investigation into the global and site-specific methylation in fetal and postnatal liver and brain in response to maternal HF and CS. Here we demonstrate an increase in DNA methylation and decrease in gene expression of Srebp1, a gene that mediates de novo lipogenesis, by maternal CS in the HF condition during the fetal period. However, this epigenetic change was not maintained in adulthood. Global DNA methylation of liver and adipose demonstrates increased methylation during the prenatal period yet decreased methylation during postnatal HF feeding of maternal CS offspring, suggesting that methylation marks established by maternal CS cannot be maintained during postnatal HF feeding.

Chapter 4 explores the lipidomic changes in the fetal and postnatal period in response to maternal HF and CS. We found increases in ether-linked phospholipids (plasmalogens) which serve as antioxidants for cellular membrane lipids in HFCS male offspring, suggesting a potential role of maternal CS in redox regulation and membrane integrity.

Chapter 5 explores the metabolic outcomes of mouse offspring exposed to prenatal HFCS and 16-weeks of postnatal western diet (WD) challenge. Results suggest that prenatal HFCS has mixed effects on offspring phenotypes and MAFLD biomarkers, and the effects were sexually dimorphic. Further, systems approaches were used to assess the transcriptomic and lipidomic changes related to maternal HFCS after the 16-week WD challenge in offspring.

Chapter 6 presents the rationale for a systems approach in interpreting the findings presented, discusses limitations in the study and future directions for research in preventing MASH (steatohepatitis) pathogenesis.

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