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. 2022 Feb 10;298(3):101709. doi: 10.1016/j.jbc.2022.101709

Figure 8.

Figure 8

Mfsd2a deficiency alters the AT2 cell lipidome reflective of changes in BAL. Lipidomic analysis of AT2aKO and 2afl/fl BAL 2 weeks post-tamoxifen treatment. Total PC 32:0 (A) and phospholipid (PL) species containing DHA (PL-DHA) (B) or AA (PL-AA) (C) were reduced in AT2aKO BAL relative to 2afl/fl. D, lipidomic analysis of AT2aKO and 2afl/fl AT2 cells 2 weeks post-tamoxifen treatment. Total PC 32:0 was reduced in AT2aKO AT2 cells relative to 2afl/fl. E, mol% lipid species represented as a volcano plot. Dots above dashed line indicate lipid species that are significantly different between AT2aKO and 2afl/fl AT2 (PL, SL, and NL. F, PLs with monounsaturated fatty acids (PL-MUFA) species were increased in AT2aKO AT2 cells relative to 2afl/fl. G, PC–DHA species were reduced in AT2aKO AT2 cells relative to 2afl/fl, similar to changes in the BAL lipidome. For A–D, data are represented as mean μmol/μl BAL ± SE, with individual points denoting biological replicates. 2afl/fl, n = 13; AT2aKO, n = 12. For F–H, data represented as mol% ± SE of PLs, with individual points denoting biological replicates. n = 7 per genotype. Unpaired t test with Welch's correction, ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. H, model to show Mfsd2a is required for surfactant homeostasis. AT2 cells synthesize surfactants, which are secreted as DPPC-rich lamellar bodies at the apical surface that unravel into large surfactant aggregates that make up the alveolar lining fluid. Spent surfactant is released as small surfactant aggregates that are hydrolyzed by sPLA2 in the alveolar space to produce lysophosphatidylcholines (LPCs). LPC are then taken up by Mfsd2a expressed at the apical surface of AT2 cells and serve as a precursor for the synthesis of PC–DHA that are then remodeled into the main surfactant PL DPPC. Some LPCs can also be cleared by alveolar macrophages. In the absence of Mfsd2a, uptake of LPCs is limited resulting in reduction in PC–DHA leading to reduced resynthesis of DPPC. Moreover, reduced sPLA2 activity in the absence of Mfsd2a might be a result of altered surfactant composition.