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.

Keywords: AGPAT; LPAAT; cancer; lipids; metabolism; phosphatidic acid.

Figure 1

Schematic overview of lipid metabolism in normal as well as cancer cells. Lipid uptake of free fatty acids (FA: saturated, unsaturated, and/or polyunsaturated fatty acids) or Low-/Very-Low-Density Lipoproteins (LDL/VLDL) is facilitated by lipoprotein lipase (LPL), receptors (LDLR/VLDLR, CD36), and FA binding proteins (FABP). De novo synthesis, fueled by acetyl-CoA derived from citrate produced in the TCA cycle, creates saturated FA (SFA) and unsaturated FA (UFA). FAs in the form of acyl-CoA are used for the synthesis of triacylglycerides (TAG) and phosphoglycerides (PG) and stored in lipid droplets (LDs). LDs can be broken down to FAs by lipolysis. FAs, after conversion to acyl-CoA, can also be transported to mitochondria and broken down to acetyl-CoA by β-oxidation. The production and oxidation of polyunsaturated FA (PUFA) in the presence of Fe²⁺ and oxidants (ROS) is directly related to cell death by ferroptosis. Lipid metabolism-related enzymes are shown as purple rectangles (see text for further details). (Abbreviations: PA (Phosphatidic Acid), Lysophosphatidic Acid (LPA), Diacylglycerol (DAG), Monoacylglycerol (MAG), short-chain acyl-coenzyme A dehydrogenase (SCAD), medium-chain acyl-coenzyme A dehydrogenase (MCAD), and long-chain acyl-coenzyme A dehydrogenase (LCAD)).

Figure 2

The AGPAT enzyme family. (A) AGPATs catalyze the conversion of LPA to PA. (B) Phylogenetic tree of AGPAT1-5. (C) Schematic representation of AGPAT isoform domain structure. The acyltransferase region is shown in grey; the four acyltransferase motifs are shown in blue. The HXXXXD signature, conferring catalytic activity, is present in the first acyltransferase motif of all isoforms. (D) Amino acid sequence alignment of the region containing the AGPAT isoforms’ HXXXXD signature. Conserved amino acids are marked by an asterisk (*).

Figure 3

Intracellular localization and function of AGPATs. Different membrane compartments are populated by specific AGPAT isoforms. Isoforms AGPAT1–4 have been localized on the endoplasmic reticulum (ER), AGPAT3, and AGPAT4 on the Golgi apparatus, and AGPAT4 and AGPAT5 on mitochondria. Phosphatidic acid (PA) synthesized via the catalytic activity of AGPATs has multiple roles in cells, promoting cancer cell survival, proliferation, and metastasis. First, PA is an intermediate for the synthesis of TAGs, which are stored in lipid droplets (LDs), protecting cancer cells from free FA toxicity and serving as energy reservoirs. Second, PA is a precursor of phosphoglycerides (PGs), essential for new membrane synthesis in rapidly proliferating cancer cells. Third, insertion of PA regulates protein–membrane interactions, causes membrane curvature, and participates in vesicular transport, mediating cancer cell metastasis.