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Enhanced hepatic cholesterol accumulation induced by maternal betaine exposure is associated with hypermethylation of CYP7A1 gene promoter

  • Nannan Zhao
  • Shu Yang
  • Yue Feng
  • Bo Sun
  • Ruqian ZhaoEmail author
Original Article



Betaine contains three methyl groups and plays a critical role in regulating glucose and lipid metabolism via epigenetic modifications. However, it is unclear whether prenatal betaine intake could affect cholesterol metabolism of progeny through DNA methylation.


Hence, pregnant rats were randomly divided into control and betaine groups fed standard diet or 1% betaine supplementation diet, respectively, throughout gestation and lactation.


Maternal betaine exposure significantly (P < 0.05) increased serum and hepatic cholesterol contents but not triglyceride levels in offspring rats. Accordantly, maternal intake of betaine markedly downregulated (P < 0.05) hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) expression at both the mRNA and protein level, while the protein content of low-density lipoprotein receptor (LDLR) was upregulated in the liver of betaine-exposed rats. In addition, prenatal betaine supplementation extremely increased (P < 0.05) hepatic betaine-homocysteine methyltransferase (BHMT) expression at the mRNA and protein level but not affected the expression of other key enzymes involved in methionine metabolism. Furthermore, hepatic hypermethylation of CYP7A1 gene promoter was observed in progeny rats derived from betaine-supplemented dams.


Our results provide evidence that maternal betaine supplementation significantly enhances hepatic cholesterol contents accompanied with alterations of cholesterol metabolic genes and hypermethylation in offspring rats at weaning.


Maternal Betaine DNA methylation Cholesterol 



The present study was supported by the National Key Research and Development Program of China (2016YFD0500502), the National Basic Research Program of China (2012CB124703), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control.

Author contributions

N.Z. contributed to hormone and gene assays, data analysis, and drafting of the manuscript. S.Y. was responsible for animal care, breeding, and sampling. Y.F. and B.S. provided technical support. R.Z. contributed to conception, experimental design, data interpretation, and critical revision of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The authors declare that handling of animals and all experimental procedures were according to “Guidelines on Ethical Treatment of Experimental Animals” (2006) No. 398 set by the Ministry of Science and Technology, China and approved by the Animal Ethics Committee of Nanjing Agricultural University.

Supplementary material

12020_2019_1906_MOESM1_ESM.docx (19 kb)
Supplementary Information


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Nannan Zhao
    • 1
    • 2
  • Shu Yang
    • 1
    • 2
  • Yue Feng
    • 1
    • 2
  • Bo Sun
    • 1
    • 2
  • Ruqian Zhao
    • 1
    • 2
    Email author
  1. 1.MOE Joint International Research Laboratory of Animal Health & Food SafetyNanjing Agricultural UniversityNanjingP. R. China
  2. 2.Key Laboratory of Animal Physiology & BiochemistryNanjing Agricultural UniversityNanjingP. R. China

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