Lclat1, also known as LYCAT, AGPAT8, LPLAT6, or ALCAT1, is an acyltransferase that plays a crucial role in regulating the fatty acyl profiles of cardiolipin and phosphatidylinositol, along with its phosphorylated derivative phosphoinositides [3]. These lipids are involved in a wide range of cellular functions such as signal transduction, membrane traffic, mitochondrial function, cytoskeletal dynamics, and cell metabolism [3].

In MDA-MB-231 and ARPE-19 cells, Lclat1 silencing abated the levels of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) in response to EGF signaling, and also impaired EGF-driven and insulin-driven Akt activation and downstream signaling, indicating its requirement for receptor tyrosine kinase signaling [1]. In prostate cancer, the long non-coding RNA DNMBP-AS1 promotes cancer development by sponging microRNA-6766-3p to regulate Lclat1 expression, and it can also stabilize Lclat1 expression by recruiting ELAV like RNA binding protein 1 (ELAVL1) [2]. In podocytes of diabetic kidney disease, increased Lclat1 (ALCAT1) expression is accompanied by increased oxidized cardiolipin and significant mitochondrial damage, and Lclat1 (ALCAT1) deficiency effectively prevents high-glucose-induced oxidized cardiolipin production and mitochondrial damage [4]. In vitro hypoxia/reoxygenation in human kidney cells leads to elevated Lclat1 gene expression and protein levels, along with increased cardiolipin levels and changes in mitochondrial function [5].

In conclusion, Lclat1 is an important acyltransferase regulating the fatty acyl profiles of key lipids, thereby influencing multiple cellular functions. Studies using loss-of-function models like gene silencing in cells or potential Lclat1 knockout mouse models (not explicitly mentioned in the references but inferred from the general approach) have revealed its significance in receptor tyrosine kinase signaling, cancer development, and mitochondrial function in disease conditions such as diabetic kidney disease. These findings contribute to understanding the biological mechanisms and provide potential therapeutic targets for related diseases.

References:

1. Chan, Victoria, Camardi, Cristina, Zhang, Kai, Antonescu, Costin N, Botelho, Roberto J. 2024. The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate generation and Akt signaling. In Molecular biology of the cell, 35, ar118. doi:10.1091/mbc.E23-09-0361. https://pubmed.ncbi.nlm.nih.gov/39024272/

2. Yin, Xiangang, Wang, Suying, Ge, Rong, Xu, Shanshan, Yang, Ting. 2023. Long non-coding RNA DNMBP-AS1 promotes prostate cancer development by regulating LCLAT1. In Systems biology in reproductive medicine, 69, 142-152. doi:10.1080/19396368.2022.2129520. https://pubmed.ncbi.nlm.nih.gov/36602957/

3. Zhang, Kai, Chan, Victoria, Botelho, Roberto J, Antonescu, Costin N. . A tail of their own: regulation of cardiolipin and phosphatidylinositol fatty acyl profile by the acyltransferase LCLAT1. In Biochemical Society transactions, 51, 1765-1776. doi:10.1042/BST20220603. https://pubmed.ncbi.nlm.nih.gov/37737061/

4. Hao, Yiqun, Fan, Yanqin, Feng, Jun, Yang, Hongxia, Ding, Guohua. 2024. ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease. In Cell communication and signaling : CCS, 22, 26. doi:10.1186/s12964-023-01399-4. https://pubmed.ncbi.nlm.nih.gov/38200543/

5. Strazdauskas, Arvydas, Trumbeckaite, Sonata, Jakstas, Valdas, Klimkaitis, Kristupas, Baniene, Rasa. 2024. In Vitro Hypoxia/Reoxygenation Induces Mitochondrial Cardiolipin Remodeling in Human Kidney Cells. In International journal of molecular sciences, 25, . doi:10.3390/ijms25116223. https://pubmed.ncbi.nlm.nih.gov/38892409/