Abstract
OBJECTIVES: Pregnant women may transmit their metabolic phenotype to offspring, enhancing the risk for non-alcoholic fatty liver disease (NAFLD) in the next generation; however, the molecular mechanisms remain unclear. In the present study, we hypothesized that the maternal HF diet disrupts one-carbon metabolism with a consequent methylation change in the offspring liver that contributes to a worsen NAFLD induced by postweaning high-fat (HF) diet. METHODS: To test our hypothesis, we used offspring mice exposed to either maternal HF diet (HF group), or an early transition to a maternal NF diet before pregnancy (H9N group), or maternal methyl donor supplement (H1S or H2S group), comparing to the offspring with normal-fat diet (NF group). RESULTS: The HF offspring displayed obesity, glucose intolerance and hepatic steatosis, the H9N offspring avoided all, while the H1S and H2S offspring released hepatic steatosis only. Data from the gene expression study suggested a disruption of pathways involved in the one-carbon metabolism in the HF offspring with a restoration in the H9N, the H1S and the H2S offspring. Furthermore, we showed a disruption of methionine cycle associated with DNA hypermethylation and a de-production of L-carnitine and PPAR-α in the HF, but not the H9N offspring. However, the H1S and H2S diet only normalized the methionine cycle and restored L-carnitine and PPAR-α content, but not rescued the DNA hypermethylation in offspring liver. Thus, we proved that the maternal HF diet disrupted the methionine cycle and further led to methylation changes for mitochondrial dysfunction and fatty acid oxidation responsible for the fatty liver, rather than for the global DNA hypermethylation, which might contribute to the obesity and glucose intolerance. CONCLUSIONS: Our study provides a novel mechanism to understand the lipid metabolism and epigenetics in transgeneration. More importantly, it suggested to us a potentially effective diet intervention strategy to reduce the transgeneration risk for NAFLD. FUNDING SOURCES: This project is supported by grants from the National Institutes of Health. This work is supported by the USDA National Institute of Food and Agriculture.