Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD

Abstract

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells ( Fasn iΔAEC2 ) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. Fasn iΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid–containing phospholipids, as well as increased BALF surface tension. Fasn iΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

“…Signaling pathways include immune system [109], signal transduction [110], extracellular matrix organization [111], adaptive immune system [112], neutrophil degranulation [113], innate immune system [114], metabolism [115], diseases of metabolism [116] and Hemostasis [117] were responsible for advancement of COPD. PTGS2 [118], IL6 [119], CSF3 [120], CXCL8 [121], CXCL1 [122], SOCS3 [123], CCL3 [124], CCL5 [125], VCAM1 [126], CXCL13 [127], CXCL5 [128], CXCL12 [129], FGG (fibrinogen gamma chain) [130], IL1B [131], AREG (amphiregulin) [132], SERPINE1 [133], OSM (oncostatin M) [134], CCL11 [135], MFAP4 [136], APLN (apelin) [137], IL1RN [138], IFNG (interferon gamma) [139], CX3CL1 [140], CDKN1A [141], ICAM1 [142], SNAI1 [143], CD34 [144], IL33 [145], FASLG (Fas ligand) [146], FGF7 [147], TNF (tumor necrosis factor) [148], GDF15 [149], CCL22 [150], IL2 [151], CXCR6 [152], KLF5 [153], MCL1 [154], SRF (serum response factor) [155], FABP4 [156], CYP2C19 [157], CXCR4 [158], FOXC1 [159], EPHX1 [160], ANXA1 [161], DUSP6 [162], CPA3 [163], MYH10 [164], ICOS (inducible T cell costimulator) [165], CD1C [166], CD96 [167], S100A9 [168], FKBP5 [169], HMOX1 [170], PRTN3 [171], MARCO (macrophage receptor with collagenous structure) [172], STAB1 [173], SIGLEC9 [174], SLC11A1 [175], BPI (bactericidal permeability increasing protein) [176], PGF (placental growth factor) [177], FASN (fatty acid synthase) [178], S100A4 […”

Therapeutic effects of fatty acid binding protein 1 in mice with pulmonary fibrosis by regulating alveolar epithelial regeneration

“…4 5 20 The major site of fat metabolism is in alveolar epithelial cells in lung, ATII cells strictly regulate lipid metabolism to maintain surfactant synthesis. 21 Fatty acids are a key component of surfactant, and their metabolism in alveolar epithelial cells is essential to produce this substance. We showed that FABP1 colocalised with the marker of type II alveolar epithelial cells SPC, and the expression of SPC increased while the restoration of FABP1 (figure 5), hinting it can increase the production of surfactant, up-regulate the expression of SPC and promote the regeneration of alveolar epithelial cells.…”

Untargeted lipidomics of bronchopulmonary dysplasia induced by hyperoxia exposure in rats

“…In addition, lipids are an important component of PSs, which reduce alveolar surface tension and prevent alveolar atrophy during exhalation. PSs are mainly synthesized by Alveolar type II epithelial (AT2) cells, but the number of proliferating AT2 cells in the lung tissue of premature infants with BPD is reduced ( 5 , 6 ). Therefore, the synthesis of PS in premature infants with BPD may be hindered.…”