Disturbed One-Carbon Metabolism Causing Adverse Reproductive Outcomes in Mice Is Associated with Altered Expression of Apolipoprotein Al and Inflammatory Mediators PPAR alpha, Interferon-gamma, and Interleukin-10

作者：Mikael Leonie G; Pancer Jill; Wu Qing; Rozen Rima^*

来源：Journal of Nutrition, 2012, 142(3): 411-418.

DOI：10.3945/jn.111.151753

Low dietary choline or deficiency of methylenetetrahydrofolate reductase (Mthfr) leads to hyperhomocysteinemia (Hhcy) and adverse reproductive outcomes. Homocysteine reduces synthesis of ApoAl, the major lipoprotein in HDL-cholesterol; ApoAl is regulated by PPAR alpha and has antiinflammatory properties. Our aim was to determine whether pregnancy complications due to genetic or nutritional deficiencies in 1-carbon metabolism could relate to dysregulation of ApoAl and inflammatory mediators. We fed pregnant mice, with or without a deficiency of Mthfr, control or choline-deficient (ChDD) diets for 10-12 wk and examined levels of ApoAl, PPAR alpha, IFN gamma, and IL-10. ApoAl mRNA was reduced in livers of Mthfr(+/-) mice and ApoAl protein was reduced due to Mthfr deficiency or choline deficiency in liver and plasma. Placental ApoAl protein was also reduced due to Mthfr genotype or choline-deficient diet and in developmentally delayed embryos. Reduced liver PPAR alpha expression (mRNA and protein) was observed in ChDD-fed mice and was associated with increased methylation of a CpG dinucleotide in its promoter. Hepatic IFN gamma increased due to genotype, and placental IFN gamma was higher in Mthfr(+/-) ChDD-fed dams compared to Mthfr(+/+) mice fed ChDD or Mthfr(+/-) mice fed CD. IL-10 was reduced in livers of ChDD-fed mice. We propose that a deficiency of dietary choline or Mthfr leads to Hhcy and reduced expression of maternal ApoAl, with reduced ApoAl transfer to embryo. Disturbances in 1-carbon metabolism also reduce maternal PPAR alpha expression, possibly through promoter hypermethylation, and increase IFN gamma and decrease IL-10 levels. This disturbance of the T helper (Th1) (IFN gamma):Th2 (IL-10) ratio and the increase in inflammatory mediators may contribute to pregnancy complications. J. Nutr. 142: 411-418, 2012.

• 出版日期2012-3
• 单位McGill