Overexpression of fatty acid synthase attenuate bleomycin induced lung injury/fibrosis via restoring mitochondrial dysfunction

Abstract

Background: Excessive alveolar epithelial cell(AEC) death by repeated injury play a role in the pathogenesis of lung fibrosis. Recently reports show defective lipid metabolism in AEC contributes to development or progression of lung fibrosis and normal lipid metabolism relies on proper mitochondrial function. Fatty acid synthase(FASN) is key enzyme catalyzes the conversion of acetyl-CoA and malonyl-CoA to saturated fatty acids. Objectives: We investigated whether regulation of FASN expression in AECs modulate severity of lung fibrosis and to find its possible mechanism. Methods: We generated FASN knock-down, overexpression stable cell lines and human FASN transgenic (TG) mice, with conditionally induced alveolar epithelium to overexpress FASN. Cell proliferation and apoptosis assay were performed treated with bleomycin(BLM). Lung fibrosis was established by BLM inhaled FASN TG mice. Measurement and Results: We found that FASN protein was mainly expressed at AECs in controls but significantly reduced in IPF lung. Knockdown of FASN significantly increased but overexpression of FASN attenuate apoptotic cell death. FASN overexpression reduces BLM-induced loss of mitochondrial membrane potential and downregulate mitochondrial ROS production. FASN TG mice dramatically attenuated BLM-induced lung inflammation and fibrosis. Conclusions: These findings suggest that defective FASN production may associated with IPF pathogenesis and augmentation of FASN in the lung may have therapeutic potential in preventing lung fibrosis. This study was supported by National research foundation of Korea grant 2019R1A2C1006351.