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

Am J Respir Cell Mol Biol. 2017 Jun;56(6):738-748. doi: 10.1165/rcmb.2016-0282OC.


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.

Keywords: CPT1A; FAM13A; cigarette smoke; fatty acid β-oxidation; mitochondria.

MeSH terms

  • Acetylation
  • Animals
  • Bronchi / pathology
  • Carnitine O-Palmitoyltransferase / metabolism
  • Cell Death
  • Cell Respiration
  • Epithelial Cells / metabolism
  • Fatty Acids / metabolism*
  • GTPase-Activating Proteins / metabolism
  • Gene Silencing
  • Humans
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Protein Binding
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Reactive Oxygen Species / metabolism
  • Sirtuin 1 / metabolism
  • Smoking / adverse effects


  • Fatty Acids
  • GTPase-Activating Proteins
  • Reactive Oxygen Species
  • CPT1A protein, human
  • Carnitine O-Palmitoyltransferase
  • Sirtuin 1