Disruption of hepatic one-carbon metabolism impairs mitochondrial function and enhances macrophage activity in methionine-choline deficient mice

Abstract One-carbon metabolism is a collection of metabolic cycles that supports methylation and provides one-carbon bound folates for the de novo synthesis of purine and thymidine nucleotides. The methylation of phosphatidylethanolamine to form choline has been extensively studied in the context of fatty liver disease. However, the role of one-carbon metabolism in supporting nucleotide synthesis during liver damage has not been addressed. The objective of this study is to determine how the disruption of one-carbon metabolism influences nucleotide metabolism in the liver after dietary methionine and choline restriction. Mice (n=8) were fed a methionine-choline deficient or control diet for three weeks. We treated mice with the compound alloxazine (0.5 mg/kg), a known adenosine receptor antagonist, every second day during the final week of feeding to probe the function of adenosine signaling during liver damage. We found concentrations of several hepatic nucleotides were significantly lower methionine and choline deficient mice versus controls (Adenine; 13.9±0.7 versus 10.1±0.6, Guanine; 1.8±0.1 versus 1.4±0.1, Thymidine; 0.0122±0.0027 versus 0.0059±0.0027 nmole/mg dry tissue). Treatment alloxazine caused a specific decrease in thymidine nucleotides and decreased mitochondrial content in the liver and exacerbation of steatohepatitis as shown by the increased hepatic lipid content and altered macrophage morphology. This study demonstrates a role for one-carbon metabolism in supporting de novo nucleotide synthesis and mitochondrial function during liver damage.