Gnpat, also known as glyceronephosphate O-acyltransferase or dihydroxyacetone phosphate-acyltransferase (EC 2.3.1.42), is a key enzyme in plasmalogen synthesis. Plasmalogens are important lipids, and their synthesis pathway is crucial for normal biological functions. Dysregulation of Gnpat has been implicated in multiple biological processes and diseases, highlighting its biological importance. Genetic models, such as knockout mice, have been valuable in studying Gnpat's function [1,2,3,4].

In mice, Gnpat-knockout (Gnpat-/-) and hepatocyte-specific Gnpat-knockout (Gnpatfl/fl;Alb-Cre) models showed that deleting Gnpat expression had no significant effect on serum iron and tissue iron levels, nor on hepcidin expression under normal or high-iron dietary conditions, suggesting that Gnpat does not directly mediate systemic iron homeostasis [2]. In adipose-specific Gnpat knockdown mice, it recapitulated the effects of Pex16 inactivation on mitochondrial morphology and function, indicating its role in regulating adipose thermogenesis by mediating cold-induced mitochondrial fission [3]. In hepatocarcinogenesis, ACAT1-mediated Gnpat acetylation at K128 represses TRIM21-mediated Gnpat ubiquitination and degradation. This stabilization of Gnpat promotes lipid metabolism and hepatocarcinogenesis, as shRNA-mediated ACAT1 ablation and acetylation-deficient Gnpat repress lipid metabolism and tumor progression in xenograft and DEN/CCl4-induced HCC models [1].

In conclusion, Gnpat plays essential roles in lipid metabolism-related processes like plasmalogen synthesis, adipose thermogenesis, and hepatocarcinogenesis. Mouse models, especially Gnpat-KO and tissue-specific CKO models, have been instrumental in revealing its functions in these areas, contributing to our understanding of related disease mechanisms [1,2,3].

References:

1. Gu, Li, Zhu, Yahui, Lin, Xi, Lu, Bingjun, Li, Youjun. 2020. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis. In Oncogene, 39, 2437-2449. doi:10.1038/s41388-020-1156-0. https://pubmed.ncbi.nlm.nih.gov/31974474/

2. An, Peng, Wang, Jiaming, Wang, Hao, Min, Junxia, Wang, Fudi. 2020. Gnpat does not play an essential role in systemic iron homeostasis in murine model. In Journal of cellular and molecular medicine, 24, 4118-4126. doi:10.1111/jcmm.15068. https://pubmed.ncbi.nlm.nih.gov/32108988/

3. Park, Hongsuk, He, Anyuan, Tan, Min, Funai, Katsuhiko, Lodhi, Irfan J. 2019. Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission. In The Journal of clinical investigation, 129, 694-711. doi:10.1172/JCI120606. https://pubmed.ncbi.nlm.nih.gov/30511960/

4. Bertolesi, Gabriel E, Chilije, Maxwell F J, Li, Victoria, Zaremberg, Vanina, McFarlane, Sarah. . Differential Eye Expression of Xenopus Acyltransferase Gnpat and Its Biochemical Characterization Shed Light on Lipid-Associated Ocular Pathologies. In Investigative ophthalmology & visual science, 64, 17. doi:10.1167/iovs.64.5.17. https://pubmed.ncbi.nlm.nih.gov/37204785/