Lipid Metabolism in Cancer: The Role of Acylglycerolphosphate Acyltransferases (AGPATs)

Abstract

Altered lipid metabolism is an emerging hallmark of aggressive tumors, as rapidly proliferating cancer cells reprogram fatty acid (FA) uptake, synthesis, storage, and usage to meet their increased energy demands. Central to these adaptive changes, is the conversion of excess FA to neutral triacylglycerides (TAG) and their storage in lipid droplets (LDs). Acylglycerolphosphate acyltransferases (AGPATs), also known as lysophosphatidic acid acyltransferases (LPAATs), are a family of five enzymes that catalyze the conversion of lysophosphatidic acid (LPA) to phosphatidic acid (PA), the second step of the TAG biosynthesis pathway. PA, apart from its role as an intermediate in TAG synthesis, is also a precursor of glycerophospholipids and a cell signaling molecule. Although the different AGPAT isoforms catalyze the same reaction, they appear to have unique non-overlapping roles possibly determined by their distinct tissue expression and substrate specificity. This is best exemplified by the role of AGPAT2 in the development of type 1 congenital generalized lipodystrophy (CGL) and is also manifested by recent studies highlighting the involvement of AGPATs in the physiology and pathology of various tissues and organs. Importantly, AGPAT isoform expression has been shown to enhance proliferation and chemoresistance of cancer cells and correlates with increased risk of tumor development or aggressive phenotypes of several types of tumors.

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

“…The increase in lipid metabolism is another hallmark because lipids are essential building blocks for cancer and viruses to create new organelles, cells, and virions [ 74 , 75 ]. Lipid synthesis is a multi-enzyme process involving many steps, usually starting with acetyl-CoA and ending in fatty acids [ 76 , 77 ]. In metabolic reprogrammed cells, the majority of acetyl-CoA for lipid synthesis comes from citrate produced by the TCA cycle, and that has been transported out of the mitochondria.…”

The prognostic value of the GPAT/AGPAT gene family in hepatocellular carcinoma and its role in the tumor immune microenvironment

“…The expression of AGPAT isoforms has been shown to enhance tumor cell proliferation and drug resistance and is associated with an increased risk of tumorigenesis or the development of aggressive phenotypes in a variety of cancers (9). Therefore, we built a machinelearning model with LASSO regression to identify the variables in this gene family that is most associated with OS in HCC and to reduces the effect of multicollinearity (44).…”

“…However, beyond PA synthesis, the specific physiological role of AGPAT5 is currently unknown. AGPAT5 may have a crucial function in mitochondrial fusion and division (9). In turn, the results of recent studies suggest that mitochondrial membrane fusion-mediated increases in oxidative phosphorylation and NADH/NAD+ metabolism contribute to tumor immortalization (46).…”

“…1-Acylglycerol-3-phosphate O-acyltransferases (AGPATs) is essential for the production of triacylglycerol (TAG), and these enzymes are also involved in the synthesis of most fatty acids (7). AGPAT isozymes reportedly promote proliferation and drug resistance in cancer cells and are associated with a high risk of tumor formation or aggressive tumor profiles (9)(10)(11)(12).…”

An integrative analysis of DNA methylation and gene expression to predict lung adenocarcinoma prognosis

“…Interestingly, in the hyper-down group, there was also gene enrichment related to fatty acid degradation (Figure 3B). The effects of lipid metabolism disorders on cancer have attracted increasing attention in recent years (Karagiota et al, 2022). There is no doubt that to reprogram their metabolic state and ensure cell survival, tumor cells need (Singh et al, 2017;Huo et al, 2021).…”