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aytl2

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Official Full Name
lysophosphatidylcholine acyltransferase 1

Lysophosphatidyl choline acyltransferase 1 (AYTL2), also known as LPCAT1, is located on the human genome at 5p15.33. It encodes a phospholipid synthesis enzyme with acyltransferase and acetyltransferase activity. AYTL2 protein is widely expressed in different types of human cells, mainly located in the endoplasmic reticulum, Golgi apparatus and lipid droplets. It is also localized in the cell membrane and nucleus in some types of cells. AYTL2 mainly deacylates and reacylates phosphatidylcholine to produce saturated phosphatidylcholine.

AYTL2 is a basic expression of lyso-PAF acetyltransferase. AYTL2 in different parts has different preferences for saturated and unsaturated fatty acyl-CoA, and AYTL2 prefers unsaturated fatty acyl-CoA in liver microsomes. In palm microsomes, it is more preferred for palmitoyl CoA than for unsaturated acyl CoAs. In recent years, it has been found that AYTL2 is involved in a variety of biological processes, including acyl chain remodeling of phosphatidylcholine and phosphatidylglycerol, cellular lipid metabolism, maintenance of surfactant homeostasis, etc. It is associated with various diseases.

Alveolar surfactant is an important component for maintaining normal respiratory function and its main component is dipalmitoyl lecithin. AYTL2 is one of dipalmitoyl lecithin synthase. Human and mouse expressed AYTL2 has lysophosphatidylcholine acyltransferase and lysophosphatidylglycerol acyltransferase (LPGAT) activity, which respectively catalyzes the production of PC and phosphatidylglycerol (PG). Lin et al. found that AYTL2 can interact with the specific phospholipid transporter StarD10 to initiate the transport of SatPC from the endoplasmic reticulum to lamellar bodies in alveolar type II cells. Welch et al. also found that the level of AYTL2 mRNA in human fetal amniotic fluid is related to the number of lamellar bodies. Due to the exchange of fetal and maternal body fluids, fetal and placental maturity can be understood by measuring the AYTL2 content in maternal plasma. AYTL2 plays an important role in the formation and transportation of alveolar surfactants. Its dysfunction is closely related to respiratory diseases including acute respiratory distress and atelectasis. It is a new entry point for the treatment of such diseases in the future.

Studies have shown that AYTL2 is highly associated with several secondary retinopathies. Plasma lyso-phosphatidylcholine (LPC) concentrations are significantly elevated in insulin-dependent and non-insulin-dependent diabetic patients and diabetic retinopathy. There are Increased levels of PAF and lyso-PAF in the serum of patients with type 1 diabetes and oxygen-induced retinopathy. PAF and LPC are potent inflammatory lipids. AYTL2 is synthesized by converting LPC to PC and catalyzing alkyl-PC (an inactive form of PAF with acyl-CoA and hemolytic lyso-PAF as a substrate) to play a role in inactivating PAF.

In Ins2Akita and db/db mice (type 1 and type 2 diabetic mouse models, respectively), AYTL2 mRNA levels and AYTL2 activity in lyso-PAF and LPC were significantly down-regulated in retina and brain tissue. After Dai et al. treated db/db mice with the anti-diabetic drug rosiglitazone, AYTL2 mRNA levels were significantly up-regulated, while AYTL2 activity in the retina and brain increased. These studies suggest that decreased AYTL2 function is associated with the development of retinal degeneration, and its expression regulation is affected by diabetes drugs. AYTL2 may be a potential target for the treatment of retinal degeneration.

AYTL2 is closely related to lipid metabolism. In mammalian cells, AYTL2 is surrounded by a monolayer of phospholipids (primarily PC), forming the core of neutral lipids. The expression level of AYTL2 is related to the ability of lipid droplets to locally synthesize PC. Interference with AYTL2 and LPCAT2 result in an increase in lipid droplet size, but there is no change in the total amount of neutral lipids, and this regulation affect the release of lipoproteins from hepatocytes. AYTL2 is also involved in abnormal processes of lipid metabolism associated with liver disease. Beilstein et al. found that knocking down AYTL2 in Huh-7.5.1 cells infected with HCV or primary human hepatocytes increased the amount of highly infectious viral particles. In cirrhotic rats, cholestasis can lead to a significant increase in lyso-PAF and PAF levels in the liver, while mRNA and protein levels of AYTL2 and Lpcat2 are significantly reduced. The cirrhosis treatment drug silybin can reduce the level of pro-inflammatory lipids and restore the activity and expression of AYTL2 and LPCAT2 in cirrhotic tissues.

Figure 1. The role of AYTL2(LPCAT1)and LPCAT2 in PAF synthesis and remodeling in liver cirrhosis. (Stanca, et al. 2013).

AYTL2 expression is elevated in a variety of tumor tissues and is positively correlated with the degree of malignancy, stage, and grade of the tumor. In lung cancer research, Kachuri et al. identified a separate lung cancer susceptibility variant in AYTL2 by investigating a large number of mutants: rs139852726. It was also found that rs139852726 was associated with telomere length in healthy individuals. AYTL2 is also involved in the development and progression of breast cancer. The expression of AYTL2 is significantly upregulated in primary breast cancer and also in fibrocystic disease. In breast cancer, its expression is significantly elevated at the margin of tumor invasion and is positively correlated with tumor grade and TNM stage. AYTL2 may be involved in the analysis of lipid expression profiles in cancerous tissues, especially the synthesis of monounsaturated fatty acid lecithin that provides energy for tumor formation and progression. The role of AYTL2 in prostate cancer has also been reported. Grupp et al. found that the expression of AYTL2 was significantly higher in metastatic prostate cancer than in the primary prostate tumor, which was significantly higher than that in advanced prostatic intraepithelial neoplasia and benign prostate tissue.

In digestive system tumors, AYTL2 expression levels were significantly higher in colorectal cancer tissues than in normal mucosa. Changes in lipid mass spectrometry are one of the characteristics of colorectal cancer. The expression of AYTL2 in gastric cancer is also higher than that in peripheral non-neoplastic mucosa, and its expression level is positively correlated with tumor differentiation of gastric cancer. The level of AYTL2 mRNA and protein in hepatocellular carcinoma tissues is more abundant than in the surrounding tissue parenchyma. In vitro experiments show that high expression of AYTL2 can enrich phosphatidylcholines (PCs) and promote cell proliferation, migration, and invasion. AYTL2 is also one of the "diagnostic features" of squamous cell esophageal cancer. In summary, AYTL2 is a valuable new tumor marker that helps early detection and treatment of various tumor types.

Reference:

  1. Lin S, Ikegami M, Moon C, et al. Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) Specifically Interacts with Phospholipid Transfer Protein StarD10 to Facilitate Surfactant Phospholipid Trafficking in Alveolar Type II Cells. Journal of Biological Chemistry, 2015, 290(30):18559-74.
  2. Welch R A, Recanati M A, Welch K C, et al. Maternal plasma LPCAT 1 mRNA correlates with lamellar body count. Journal of Perinatal Medicine, 2017.
  3. Dai X, Han J, Qi Y, et al. AAV-Mediated Lysophosphatidylcholine Acyltransferase 1 (Lpcat1) Gene Replacement Therapy Rescues Retinal Degeneration in rd11 Mice. Investigative Ophthalmology & Visual Science, 2014, 55(3):1724.
  4. Beilstein F, Lemasson M, Pène V, et al. Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles. Gut, 2016:gutjnl-2016-311508.
  5. Kachuri L, Amos C I, Mckay J D, et al. Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer, susceptibility loci. Carcinogenesis, 2015, 37(1):96.
  6. Grupp K, Sanader S, Sirma H, et al. High lysophosphatidylcholine acyltransferase 1 expression independently predicts high risk for biochemical recurrence in prostate cancers. Molecular Oncology, 2013, 7(6):1001-1011.
  7. Stanca E, Serviddio G, Bellanti F, et al. Down-regulation of LPCAT expression increases platelet-activating factor level in cirrhotic rat liver: potential antiinflammatory effect of silybin. Biochimica Et Biophysica Acta, 2013, 1832(12):2019-2026.