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. 2023 Jan 27;11:1104725. doi: 10.3389/fcell.2023.1104725

FIGURE 2.

FIGURE 2

Emerging pathways of PUFA channeling from membranes to lipid droplets (LDs). The redistribution of PUFAs into TAGs stored within LDs can occur via at least two conceptually distinct lipid remodeling pathways driven by PLA2 and PLD enzymes. PLA2-catalysed phospholipid hydrolysis liberates membrane resident PUFAs, which are released into the cytosol. To re-enter any metabolic or remodeling pathways, including the Kennedy pathway of de novo phospholipid and TAG biosynthesis, PUFAs have to be first converted into active PUFA-CoA intermediates by CoA synthetase enzymes, such as ACSL4, which shows preference for PUFAs, whereas the activation of MUFAs is preferentially handled by ACSL3. On the other hand, PLD-catalyzed hydrolysis of PUFA-rich phospholipids generates PUFA-containing PA, which remains confined to the 2D space of the membrane bilayer. This in principle enables a more efficient channeling of the PUFA acyl chain into TAGs via the Kennedy pathway by the sequential action of lipin and DGAT1 enzymes within the ER membrane. PUFA-PA can also be formed de novo via the AGPAT3 enzyme with known preference for PUFAs. In principle, with the help of LD-associated ACSL4, free PUFAs can also be converted into PUFA-TAGs by the DGAT2 enzyme, which can relocate from the ER to LDs to catalyze local LD expansion. In addition, PA formed by PLD can participate in lipid droplet formation and expansion by PLIN3 recruitment. Cofactors and by-products are omitted. ACSL3: acyl-CoA synthetase long chain family member 3; ACSL4: acyl-CoA synthetase long chain family member 4; AGPAT3 (also known as LPAAT3): 1-acyl-sn-glycerol-3-phosphate acyltransferase gamma; CoA: coenzyme A; DAG: diacylglycerol; DGAT1: diacylglycerol acyltransferase 1; ER: endoplasmic reticulum; LPCAT3: lysophosphatidylcholine acyltransferase 3; MUFA: monounsaturated fatty acid; PA: phosphatidic acid; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PLA2: phospholipase A2; PLD: phospholipase D; PLIN3: perilipin 3 PS: phosphatidylserine; PUFA: polyunsaturated fatty acid; sPLA2: secreted phospholipase A2; TAG: triacylglycerol.