Gpam-KO Mouse

GPAM, also known as glycerol-3-phosphate acyltransferase, mitochondrial, is a key enzyme. It catalyzes an essential step in the biosynthesis of glycerolphospholipids and triacylglycerol [4]. As a rate-limiting enzyme in the lysophosphatidic acid (LPA) synthesis pathway, it converts glycerol-3-phosphate to LPA [1]. Genetic models, such as gene knockout models, are valuable for studying its functions.

In acute myeloid leukemia (AML), GPAM is highly expressed. Silencing GPAM or using a GPAM-inhibitor (FSG67) significantly impairs AML cell propagation. This occurs through the induction of mitochondrial fission, suppression of oxidative phosphorylation, and elevation of reactive oxygen species. Notably, FSG67 administration does not affect normal human hematopoiesis in vivo, suggesting GPAM-mediated LPA synthesis is a critical metabolic mechanism regulating mitochondrial dynamics in AML [1]. In non-alcoholic fatty liver disease (NAFLD), rare, protective, predicted loss-of-function variants in GPAM have been identified, highlighting it as a potential drug target [2]. In cholangiocarcinoma (CCA), the lnc-PKD2-2-3/miR-328/GPAM ceRNA network promotes CCA cell proliferation, invasion, and 5-FU chemoresistance [3].

In conclusion, GPAM plays essential roles in lipid-related metabolic pathways. Its study using gene knockout models has revealed its significance in diseases like AML, NAFLD, and CCA. Understanding GPAM's functions provides potential therapeutic targets for these diseases.

References:

1. Irifune, Hidetoshi, Kochi, Yu, Miyamoto, Toshihiro, Akashi, Koichi, Kikushige, Yoshikane. 2023. GPAM mediated lysophosphatidic acid synthesis regulates mitochondrial dynamics in acute myeloid leukemia. In Cancer science, 114, 3247-3258. doi:10.1111/cas.15835. https://pubmed.ncbi.nlm.nih.gov/37197765/

2. Sveinbjornsson, Gardar, Ulfarsson, Magnus O, Thorolfsdottir, Rosa B, Holm, Hilma, Stefansson, Kari. 2022. Multiomics study of nonalcoholic fatty liver disease. In Nature genetics, 54, 1652-1663. doi:10.1038/s41588-022-01199-5. https://pubmed.ncbi.nlm.nih.gov/36280732/

3. Zhang, Lei, Ma, Donglai, Li, Fujun, Sun, Dongsheng, Zeng, Zhaolin. 2022. Lnc-PKD2-2-3/miR-328/GPAM ceRNA Network Induces Cholangiocarcinoma Proliferation, Invasion and 5-FU Chemoresistance. In Frontiers in oncology, 12, 871281. doi:10.3389/fonc.2022.871281. https://pubmed.ncbi.nlm.nih.gov/35965521/

4. Sun, Chuanbo, Li, Bing, Yang, Miaomiao, Wang, Jichang, Hu, Hao. 2021. Generation of GPAM knockout human embryonic stem cell line SYSUe-008-A using CRISPR/Cas9. In Stem cell research, 53, 102303. doi:10.1016/j.scr.2021.102303. https://pubmed.ncbi.nlm.nih.gov/33831647/