HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 35/2/182    most recent 00294.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kitami, T. Articles by Nadeau, J. H. PubMed PubMed Citation Articles by Kitami, T. Articles by Nadeau, J. H.

Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice

¹ Department of Genetics, Case Western Reserve University, Cleveland, Ohio
² Center for Computational Genomics and Systems Biology, Case Western Reserve University, Cleveland, Ohio
³ The Institute for Genomic Research, Rockville, Maryland
⁴ Dana-Farber Cancer Institute and Harvard School of Public Health, Department of Biostatistics and Computational Biology, Boston, Massachusetts
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas

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 with 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.