Metabolic Alterations in Mice Lacking a Major Folate Catabolic Enzyme

Abstract

Aldh1l1 (10‐formyltetrahydrofolate dehydrogenase, FDH) is a major folate enzyme, regulating the overall flow of one‐carbon groups towards biosynthetic processes. We have generated mice with the targeted knockout of Aldh1l1 and characterized their metabolic and protein expression profiles using the metabolomics approach and NanoString technology. We have observed that KO mice have significantly elevated 10‐formyltetrahydrofolate and depleted tetrahydrofolate pools in the liver, in agreement with Aldh1l1 catalytic function. The total liver folate was depleted in KO mice, which could indicate the lack of folate protection function proposed for Aldh1l1. In agreement with this decrease, levels of formiminogluatmate were elevated in KO mice implying the functional folate deficiency. Interestingly, the total folate in blood (represented mostly by 5‐methyltetrahydrofolate) was not changed. The metabolomics approach revealed changes in serine and glycine metabolism in these mice, as well as broad alterations in lipid metabolites. In agreement with the proposed function of Aldh1l1 as a candidate tumor suppressor, significant alterations in tumorigenesis‐related genes and pathways were observed including the elevation of mRNA levels of TGFb family members, certain transcription factors, and enzymes implicated in cancer cell metabolism (most noticeably glucose‐6‐phosphate dehydrogenase and phosphofructokinase). Furthermore, decreased protein levels of p53, JNK2 and CerS6, previously reported as mediators of Aldh1l1 metabolic effects, were seen in livers of Aldh1l1 KO mice. These findings underscore Aldh1l1 as a crucial regulator of metabolic pathways in mammalian cells. This work was supported by NIH grant DK54388.