Etnppl, or ethanolamine-phosphate phospho-lyase, is a metabolic enzyme that catalyzes phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde. It is involved in the catabolism of phosphoethanolamine, an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) biosynthesis [5,6,7,8]. It has been associated with multiple biological processes, including lipid metabolism, and its role has been explored in various disease-related contexts [1,2,3,4,6,8]. Genetic models, such as knockout mice, have been crucial in understanding its functions.

Whole-body Etnppl knockout mice studies showed that Etnppl has a role in regulating plasma lipoprotein metabolism independent of hepatic triglyceride (TG) levels. Primary hepatocytes from Etnppl-/-mice had increased conversion of [3H]ethanolamine to [3H]p-ETN and [3H]PE. Etnppl-/-mice had elevated fasting levels of total plasma cholesterol, TG, and apolipoprotein B100. Also, in Huh7 cells with stable transfection of Etnppl, there was reduced cellular pEtn from ethanolamine, decreased PE synthesis, increased neutral lipid storage, decreased ATP production, and slower cell proliferation [7,8]. In liver-related studies, in vitro models in human HepG2 cells and mouse AML12 cells showed that ETNPPL expression is elevated in palmitic acid (PA)-induced insulin resistance (IR), and silencing ETNPPL ameliorates this IR. Overexpressing ETNPPL promotes IR, reactive oxygen species (ROS) generation, and ARG2 activation. In hyperinsulinemia-induced IR models in HepG2 cells and primary mouse hepatocytes, ETNPPL expression was upregulated, and silencing it ameliorated IR. Overexpressing ETNPPL promoted IR, ROS generation, and AKT inactivation [1,2].

In conclusion, Etnppl is important in lipid metabolism and lipoprotein regulation. Its role in liver-related metabolic disorders like insulin resistance and hepatocellular carcinoma has been highlighted through model-based research. The Etnppl KO mouse models have been instrumental in understanding its functions in plasma lipoprotein metabolism and hepatic lipid-related processes, providing insights into potential therapeutic targets for metabolic diseases [1,2,3,7,8].

References:

1. Wang, Caihua, Li, Xiaofang, Zhang, Wei, Xiong, Yuyan, Qian, Lu. 2023. ETNPPL impairs autophagy through regulation of the ARG2-ROS signaling axis, contributing to palmitic acid-induced hepatic insulin resistance. In Free radical biology & medicine, 199, 126-140. doi:10.1016/j.freeradbiomed.2023.02.017. https://pubmed.ncbi.nlm.nih.gov/36841363/

2. Chen, Xueyi, Liu, Ping, Zhang, Wei, Xiong, Yuyan, Qian, Lu. 2023. ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes. In Journal of cellular physiology, 238, 1046-1062. doi:10.1002/jcp.30993. https://pubmed.ncbi.nlm.nih.gov/36924049/

3. Zhang, Yun, Shen, Li, Wang, Bojun, Wu, Xiaohong. 2023. Ethanolamine-phosphate phospho-lyase (ETNPPL) contributes to the diagnosis, prognosis, and therapy of hepatocellular carcinoma. In PeerJ, 11, e15834. doi:10.7717/peerj.15834. https://pubmed.ncbi.nlm.nih.gov/37637156/

4. Schillaci, Francesca A, Lanza, Giuseppe, Salluzzo, Maria Grazia, Ferri, Raffaele, Salemi, Michele. 2024. The Role of ETNPPL in Dopaminergic Neuron Stability: Insights from Neuromelanin-Associated Protein Expression in Parkinson's Disease. In International journal of molecular sciences, 25, . doi:10.3390/ijms252313107. https://pubmed.ncbi.nlm.nih.gov/39684817/

5. White, Cory J, Ellis, Jessica M, Wolfgang, Michael J. 2021. The role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis. In The Journal of biological chemistry, 297, 100830. doi:10.1016/j.jbc.2021.100830. https://pubmed.ncbi.nlm.nih.gov/34048714/

6. Leventoux, N, Augustus, M, Azar, S, Rigau, V, Hugnot, J P. 2020. Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth. In Scientific reports, 10, 5504. doi:10.1038/s41598-020-62145-1. https://pubmed.ncbi.nlm.nih.gov/32218467/

7. A Elmihi, Kholoud, Leonard, Kelly-Ann, Nelson, Randy, Clugston, Robin D, Jacobs, René L. . The emerging role of ethanolamine phosphate phospholyase in regulating hepatic phosphatidylethanolamine and plasma lipoprotein metabolism in mice. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38, e70063. doi:10.1096/fj.202401321R. https://pubmed.ncbi.nlm.nih.gov/39312446/

8. Holdaway, Courtney M, Leonard, Kelly-Ann, Nelson, Randal, Lehner, Richard, Jacobs, Rene L. 2025. Alterations in phosphatidylethanolamine metabolism impacts hepatocellular lipid storage, energy homeostasis, and proliferation. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1870, 159608. doi:10.1016/j.bbalip.2025.159608. https://pubmed.ncbi.nlm.nih.gov/40154596/