title: Genetic Control of Fatty Acid β-Oxidation in Chronic Obstructive Pulmonary Disease.
abstract: Bioenergetics homeostasis is important for cells to sustain normal functions and defend against injury. The genetic controls of bioenergetics homeostasis, especially lipid metabolism, remain poorly understood in chronic obstructive pulmonary disease (COPD), the third leading cause of death in the world. Additionally, the biological function of most of the susceptibility genes identified from genome-wide association studies (GWASs) in COPD remains unclear. Here, we aimed to address (1) how fatty acid oxidation (FAO), specifically β-oxidation, a key lipid metabolism pathway that provides energy to cells, contributes to cigarette smoke (CS)-induced COPD; and (2) whether-and if so, how-FAM13A (family with sequence similarity 13 member A), a well-replicated COPD GWAS gene, modulates the FAO pathway. We demonstrated that CS induced expression of carnitine palmitoyltransferase 1A (CPT1A), a key mitochondrial enzyme for the FAO pathway, thereby enhancing FAO. Pharmacological inhibition of FAO by etomoxir blunted CS-induced reactive oxygen species accumulation and cell death in lung epithelial cells. FAM13A promoted FAO, possibly by interacting with and activating sirutin 1, and increasing expression of CPT1A. Furthermore, CS-induced cell death was reduced in lungs from Fam13a-/-mice. Our results suggest that FAM13A, the COPD GWAS gene, shapes the cellular metabolic response to CS exposure by promoting the FAO pathway, which may contribute to COPD development.
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Departments of 2 Genetics and Complex Diseases, and.|3 Nutrition, Division of Biological Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, and.
authors.forename: Nelson H
authors.initials: NH
authors.lastname: Knudsen
authors.affiliation: 4 Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Zun Zar Chi
authors.initials: ZZC
authors.lastname: Naing
authors.affiliation: 5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.affiliation: 5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.
authors.forename: Xingbin
authors.initials: X
authors.lastname: Ai
authors.affiliation: Departments of 2 Genetics and Complex Diseases, and.|3 Nutrition, Division of Biological Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, and.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
authors.affiliation: 1 Channing Division of Network Medicine and.|5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.
authors.forename: Xiaobo
authors.identifier: 0000-0002-7127-2869
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000107:Acetylation; D000818:Animals; D001980:Bronchi / Q000473:pathology; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D016923:Cell Death; D019069:Cell Respiration; D004847:Epithelial Cells / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects
chemical_list: D005227:Fatty Acids; D020690:GTPase-Activating Proteins; D017382:Reactive Oxygen Species; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D056564:Sirtuin 1
keywords: CPT1A; FAM13A; cigarette smoke; fatty acid β-oxidation; mitochondria