Agpat4, also known as Lysophosphatidic Acid Acyltransferase Delta (LPAATδ), is an enzyme that catalyzes the formation of phosphatidic acid (PA) from lysophosphatidic acid (LPA) and acyl-CoA. It is mainly located in the trans-Golgi network membranes and mitochondrial outer membranes. PA, the product of Agpat4, is involved in cell signaling and membrane remodeling, and Agpat4 is an essential component of the membrane fission-inducing machinery [3].

In endometriosis, Agpat4 is significantly upregulated in ectopic tissues and serum samples. Reducing its expression impairs the proliferation, invasion, and migration of endometrial stromal cells, affecting key signaling molecules like Wnt3a, β-Catenin, MMP-9, and SNAI2 [1]. In colorectal cancer, Agpat4 is aberrantly expressed. Silencing it in CRC cells suppresses tumor growth in xenograft models by polarizing macrophages to an M1-like phenotype through the LPA/p38/p65 signaling axis [2].

In Agpat4-deficient mice, there are various phenotypes. In epididymal white adipose tissue, there is an increase in mass and total TAG content, with reduced TAG hydrolase activity [4]. In skeletal muscle, it impairs maximal force contractility in soleus and alters fiber type in extensor digitorum longus muscle [5]. In the brain, it regulates the levels of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, and its deficiency leads to impaired learning and memory, likely due to reduced NMDA and AMPA receptors [6,7]. Middle-aged Agpat4-deficient mice have lower body weights, elevated oxygen consumption, carbon dioxide production, and energy expenditure [8].

In conclusion, Agpat4 plays crucial roles in multiple biological processes such as lipid metabolism, cell proliferation, invasion, and migration. Its deficiency in mouse models reveals its significance in diseases like endometriosis and colorectal cancer, as well as in normal physiological functions related to adipose tissue, muscle, and the brain. These findings highlight the potential of targeting Agpat4-related pathways for therapeutic intervention in relevant diseases.

References:

1. Chen, Jun, Shen, Licong, Wu, Tingting, Yang, Yongwen. 2024. Unraveling the significance of AGPAT4 for the pathogenesis of endometriosis via a multi-omics approach. In Human genetics, 143, 1163-1174. doi:10.1007/s00439-024-02681-2. https://pubmed.ncbi.nlm.nih.gov/38850428/

2. Zhang, Dapeng, Shi, Rongchen, Xiang, Wei, Dai, Rongyang, Miao, Hongming. 2020. The Agpat4/LPA axis in colorectal cancer cells regulates antitumor responses via p38/p65 signaling in macrophages. In Signal transduction and targeted therapy, 5, 24. doi:10.1038/s41392-020-0117-y. https://pubmed.ncbi.nlm.nih.gov/32296017/

3. Zhukovsky, Mikhail A, Filograna, Angela, Luini, Alberto, Corda, Daniela, Valente, Carmen. 2019. The Structure and Function of Acylglycerophosphate Acyltransferase 4/ Lysophosphatidic Acid Acyltransferase Delta (AGPAT4/LPAATδ). In Frontiers in cell and developmental biology, 7, 147. doi:10.3389/fcell.2019.00147. https://pubmed.ncbi.nlm.nih.gov/31428612/

4. Mardian, Emily B, Bradley, Ryan M, Aristizabal Henao, Juan J, Stark, Ken D, Duncan, Robin E. 2017. Agpat4/Lpaatδ deficiency highlights the molecular heterogeneity of epididymal and perirenal white adipose depots. In Journal of lipid research, 58, 2037-2050. doi:10.1194/jlr.M079152. https://pubmed.ncbi.nlm.nih.gov/28814640/

5. Bradley, Ryan M, Bloemberg, Darin, Aristizabal Henao, Juan J, Quadrilatero, Joe, Duncan, Robin E. 2018. Lpaatδ/Agpat4 deficiency impairs maximal force contractility in soleus and alters fibre type in extensor digitorum longus muscle. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1863, 700-711. doi:10.1016/j.bbalip.2018.04.001. https://pubmed.ncbi.nlm.nih.gov/29627383/

6. Bradley, Ryan M, Marvyn, Phillip M, Aristizabal Henao, Juan J, Stark, Ken D, Duncan, Robin E. 2015. Acylglycerophosphate acyltransferase 4 (AGPAT4) is a mitochondrial lysophosphatidic acid acyltransferase that regulates brain phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol levels. In Biochimica et biophysica acta, 1851, 1566-76. doi:10.1016/j.bbalip.2015.09.005. https://pubmed.ncbi.nlm.nih.gov/26417903/

7. Bradley, Ryan M, Mardian, Emily B, Bloemberg, Darin, Quadrilatero, Joe, Duncan, Robin E. 2017. Mice Deficient in lysophosphatidic acid acyltransferase delta (Lpaatδ)/acylglycerophosphate acyltransferase 4 (Agpat4) Have Impaired Learning and Memory. In Molecular and cellular biology, 37, . doi:10.1128/MCB.00245-17. https://pubmed.ncbi.nlm.nih.gov/28807933/

8. Tomczewski, Michelle Victoria, Fernandes, Maria Fernanda, Grewal, Rajan Singh, Duncan, Robin Elaine. 2022. Middle-Aged Lpaatδ-Deficient Mice Have Altered Metabolic Measures. In Life (Basel, Switzerland), 12, . doi:10.3390/life12111717. https://pubmed.ncbi.nlm.nih.gov/36362872/