Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

Rubio-Aliaga I, de Roos B, Sailer M, McLoughlin GA, Boekschoten MV, van Erk M, Bachmair EM, van Schothorst EM, Keijer J, Coort SL, Evelo C, Gibney MJ, Daniel H, Muller M, Kleemann R, Brennan L. Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention. Physiol Genomics 43: 408-416, 2011. First published February 8, 2011; doi:10.1152/physiolgenomics.00179.2010.-Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.