Submitted on December 15, 2007
Accepted on August 4, 2008
Gene-Environment Interactions Reveal a Homeostatic Role for
Cholesterol Metabolism During Dietary Folate Perturbation in Mice
Toshimori Kitami1, Renee Rubio2, William O'Brien3, John Quackenbush2, and Joseph H Nadeau1*
1 Genetics, Case Western Reserve University, Cleveland, Ohio, United States
2 Biostatistics, Dana Farber Cancer Institute, Boston, Massachusetts, United States
3 Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: jhn4{at}case.edu.
Dietary folate supplementation can dramatically reduce the severity and incidence of several common birth defects and adult diseases that are associated with anomalies in homocysteine and folate metabolism. The common polymorphisms that adversely affect these metabolic pathways do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test involvement of folate, homocysteine and other pathways in disease pathogenesis and treatment response, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE-deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting that homeostasis among the homocysteine, folate and cholesterol metabolic pathways contributes to the beneficial effects of dietary folate supplementation.
