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Metabolic Effects of ALDH1L1 Knockout in Diethylnitrosamine‐Induced Model of Liver Carcinogenesis
Author(s) -
Sharma Jaspreet,
Krupenko Natalia,
Sumner Susan,
Krupenko Sergey
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04079
Subject(s) - carcinogenesis , carcinogen , oxidative stress , glutathione , downregulation and upregulation , isozyme , chemistry , biology , gene , biochemistry , enzyme
Background Global gene expression profiling identified ALDH1L1 (aldehyde dehydrogenase 1 family member L1, or cytosolic 10‐formyltetrahydrofolate dehydrogenase) as one of the most under expressed genes in HCCs compared to normal liver (1). ALDH1L1 is an abundant enzyme in folate metabolism representing about 1% of total soluble protein in hepatocytes. Expression of this protein is strongly and ubiquitously downregulated in human cancers through the promoter methylation. Aim The goal of this study was to analyze changes in metabolic profiles of mouse livers depending on ALDH1L1 status in a diethyl nitrosamine (DEN)‐induced model of liver carcinogenesis. Methods Fifteen‐days‐old male Aldh1l1 ‐/‐ mice and their wild‐type littermate controls ( Aldh1l1 +/+ ) were injected intraperitoneally with DEN at the dose of 15 mg/kg body weight. Individual liver samples were collected after 10‐ and 20‐weeks following treatment with DEN and subjected to metabolomics analysis in equivalent manner across multiple analytical platforms. Results Principal component analysis (PCA) showed that the differences in metabotypes between KO and WT mice were more prominent at 20 weeks then at 10 weeks. Several major cellular pathways contributed to the separation between Aldh1l1 +/+ and Aldh1l1 ‐/‐ mice in their metabolic responses to DEN including pathways of folate, glycine, lipids and carbohydrates. Additionally, changes in redox‐active compounds showed increased oxidative stress/decreased antioxidant capacity in KO livers. Conclusion Metabolic changes in KO livers support enhanced cell proliferation and reveal how the ALDH1L1 loss provides metabolic advantage for rapidly proliferating cells. References Tackels‐Horne, D.; Goodman, M.D.; Williams, A.J.; Wilson, D.J.; Eskandari, T.; Vogt, L.M.; Boland, J.F.; Scherf, U.; Vockley, J.G. Identification of differentially expressed genes in hepatocellular carcinoma and metastatic liver tumors by oligonucleotide expression profiling. Cancer 2001, 92, 395‐405.