Disturbed one-carbon metabolism causing adverse reproductive outcomes in mice is associated with altered expression of apolipoprotein AI and inflammatory mediators PPARα, interferon-γ, and interleukin-10.

Abstract

Low dietary choline or deficiency of methylenetetrahydrofolate reductase (Mthfr) leads to hyperhomocysteinemia (Hhcy) and adverse reproductive outcomes. Homocysteine reduces synthesis of ApoAI, the major lipoprotein in HDL-cholesterol; ApoAI is regulated by PPARα 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 ApoAI 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 ApoAI, PPARα, IFNγ, and IL-10. ApoAI mRNA was reduced in livers of Mthfr(+/-) mice and ApoAI protein was reduced due to Mthfr deficiency or choline deficiency in liver and plasma. Placental ApoAI protein was also reduced due to Mthfr genotype or choline-deficient diet and in developmentally delayed embryos. Reduced liver PPARα expression (mRNA and protein) was observed in ChDD-fed mice and was associated with increased methylation of a CpG dinucleotide in its promoter. Hepatic IFNγ increased due to genotype, and placental IFNγ 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 ApoAI, with reduced ApoAI transfer to embryo. Disturbances in 1-carbon metabolism also reduce maternal PPARα expression, possibly through promoter hypermethylation, and increase IFNγ and decrease IL-10 levels. This disturbance of the T helper (Th1) (IFNγ):Th2 (IL-10) ratio and the increase in inflammatory mediators may contribute to pregnancy complications.

• Authors: Leonie G Mikael, Jill Pancer, Qing Wu, Rima Rozen
• Journal: The Journal of nutrition (J Nutr) Vol. 142 Issue 3 Pg. 411-8 (Mar 2012) ISSN: 1541-6100 [Electronic] United States
• PMID: 22259189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• IL10 protein, mouse
• Inflammation Mediators
• PPAR alpha
• RNA, Messenger
• Homocysteine
• Interleukin-10
• Interferon-gamma
• Methylenetetrahydrofolate Reductase (NADPH2)

Topics

• Animals
• Apolipoprotein A-I (blood, genetics, metabolism)
• Choline Deficiency (complications, metabolism)
• DNA Methylation
• Female
• Gene Expression
• Homocysteine (blood, metabolism)
• Homocystinuria (complications, genetics, metabolism)
• Hyperhomocysteinemia (complications, metabolism)
• Inflammation Mediators (blood, metabolism)
• Interferon-gamma (metabolism)
• Interleukin-10 (metabolism)
• Liver (metabolism)
• Male
• Methylenetetrahydrofolate Reductase (NADPH2) (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Muscle Spasticity (complications, genetics, metabolism)
• PPAR alpha (genetics, metabolism)
• Placenta (metabolism)
• Pregnancy
• Pregnancy Complications (etiology, genetics, metabolism)
• Promoter Regions, Genetic
• Psychotic Disorders (complications, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)