Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease.

Abstract

BACKGROUND & AIMS:

Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear.

METHODS:

Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes.

RESULTS:

The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers.

CONCLUSIONS:

Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.

• Authors: Hui Peng, Huiting Xu, Jie Wu, Jiangyuan Li, Yi Zhou, Zehuan Ding, Stefan K Siwko, Xianglin Yuan, Kevin L Schalinske, Gianfranco Alpini, Ke K Zhang, Linglin Xie
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 41 Issue 6 Pg. 1305-1319 (06 2021) ISSN: 1478-3231 [Electronic] United States
• PMID: 33529448 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Carbon

Topics

• Animals
• Carbon (metabolism)
• Diet, High-Fat (adverse effects)
• Female
• Humans
• Lipid Metabolism
• Liver (metabolism)
• Mice
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• Pregnancy
• Prenatal Exposure Delayed Effects