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Genetic Control of Fatty Acid β-oxidation in Chronic Obstructive Pulmonary Disease.

Genetic Control of Fatty Acid β-oxidation in Chronic Obstructive Pulmonary Disease.
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Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZ, Bai Y, Ai X, Lee CH, Zhou X,


Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZ, Bai Y, Ai X, Lee CH, Zhou X, (click to view)

Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZ, Bai Y, Ai X, Lee CH, Zhou X,

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American journal of respiratory cell and molecular biology 2017 02 15() doi 10.1165/rcmb.2016-0282OC
Abstract

Bioenergetics homeostasis is important for cells to sustain normal functions and defend against injury. Genetics controls on bioenergetics homeostasis, especially lipid metabolism remain poorly understood in chronic obstructive pulmonary diseases (COPD), the third leading cause of death in the world. Additionally, biological function of most susceptible genes identified from genome-wide association studies (GWAS) in COPD remains unclear. Here, we aim to address 1) how fatty acid oxidation, specifically β-oxidation (FAO), a key lipid metabolism pathway that provides energy to cells, contributes to cigarette smoke (CS)-induced COPD; and 2) whether and how FAM13A (family with sequence similarity 13 member A), a well-replicated COPD GWAS gene, modulates FAO pathway. We demonstrated that CS induced expression of carnitine palmitoyltransferase 1A (CPT1A), a key mitochondrial enzyme for FAO pathway, thereby enhancing FAO. Pharmacological inhibition of FAO by etomoxir ameliorated CS-induced reactive oxygen species (ROS) accumulation and cell death in lung epithelial cells. Furthermore, FAM13A promotes FAO, possibly by interacting and activating sirutin 1 (SIRT1) and increasing expression of CPT1A. Consistently, transmission electron microscopy demonstrated accumulation of lipid droplets in the airway Club cells from Fam13a-/- mice, suggesting dysregulated lipid metabolism in airway epithelial cells from Fam13a-/- mice. Furthermore, CS-induced cell death was reduced in lungs from Fam13a-/- mice. Our results suggested that FAM13A, the COPD GWAS gene, shapes cellular metabolic response to CS exposure through promoting FAO pathway that may contribute to COPD development.

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