Effects of Aldh1l2 Knockout on the Metabolic Profile of Mouse Liver

Abstract

ALDH1L2 (10‐formyltetrahydrofolate dehydrogenase), an enzyme involved in folate metabolism, resides in mitochondria where it converts 10‐formyl‐THF (tetrahydrofolate) to THF and CO2 in a NADP+‐dependent reaction. Though the enzyme could be an important contributor to the NADPH pool in mitochondria, its overall biological significance is not well understood. We have generated mice with a targeted Aldh1l2 knockout and demonstrated that the enzyme is involved in the regulation of lipid metabolism in the liver. Hepatic tissues from 12–14‐weeks‐old Aldh1l2+/+, Aldh1l2+/− and Aldh1l2−/− male mice were profiled to identify metabolite changes and to pinpoint associated pathways. Global metabolomic analysis was performed by Metabolon Inc. (Durham, NC) using Ultrahigh Performance Liquid Chromatography‐Tandem Mass Spectroscopy (UPLC‐MS/MS) for five samples from each group. Levels of 105 metabolites were decreased and levels of 162 metabolites were elevated in the Aldh1l2−/− compared to Aldh1l2+/+ mice. This analysis also found a Aldh1l2 gene‐dosage effect on the liver metabotype. Notably, no effect of the KO on levels of folate was seen. Metabolites that strongly contribute to the differentiation of the Aldh1l2+/+ and Aldh1l2−/− groups are involved in cysteine, glutathione, citric acid and fatty acid metabolism. Also, levels of intermediates in the CoA biosynthesis pathway, as well as levels of CoA itself, were significantly decreased in the livers of knockout mice. Together with the increased levels of several acylcarnitines seen in the KO mice, these findings indicate impaired mitochondrial beta‐oxidation of fatty acids. This conclusion is supported by histological analysis, which revealed accumulation of lipid vesicles in the livers of KO mice. Overall, our study shows that Aldh1l2 is a key regulator of lipid metabolism in the liver.Support or Funding InformationThese studies were supported by the National Institutes of Health grant DK054388 and CA095030( to S.A.K.)