ABCA3 protects alveolar epithelial cells against free cholesterol induced cell death

Biochim Biophys Acta. 2015 Jul;1851(7):987-95. doi: 10.1016/j.bbalip.2015.03.004. Epub 2015 Mar 25.


Diffuse parenchymal lung diseases (DPLDs) are characterized by chronic inflammation and fibrotic remodeling of the interstitial tissue. A small fraction of DPLD cases can be genetically defined by mutations in certain genes, with ABCA3 being the gene most commonly affected. However, the pathomechanisms underlying ABCA3-induced DPLD are far from clear. To investigate whether ABCA3 plays a role in cellular cholesterol homeostasis, phospholipids, free cholesterol, and cholesteryl esters were quantified in cells stably expressing ABCA3 using mass spectrometry. Cellular free cholesterol and lipid droplets were visualized by filipin or oil red staining, respectively. Expression of SREBP regulated genes was measured using qPCR. Cell viability was assessed using the XTT assay. We found that wild type ABCA3 reduces cellular free cholesterol levels, induces the SREBP pathway, and renders cells more resistant to loading with exogenous cholesterol. Moreover, ABCA3 mutations found in patients with DPLD interfere with this protective effect of ABCA3, resulting in free cholesterol induced cell death. We conclude that ABCA3 plays a previously unrecognized role in the regulation of cellular cholesterol levels. Accumulation of free cholesterol as a result of a loss of ABCA3 export function represents a novel pathomechanism in ABCA3-induced DPLD.

Keywords: ABC transporter; ABCA3; Cholesterol; Diffuse parenchymal lung disease; Pulmonary surfactant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / physiology*
  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / physiology
  • Cell Death / drug effects
  • Cells, Cultured
  • Cholesterol / metabolism
  • Cholesterol / pharmacology*
  • Cytoprotection / drug effects
  • Cytoprotection / genetics*
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology
  • Humans
  • Lipid Metabolism / genetics
  • Lung Diseases, Interstitial / genetics
  • Lung Diseases, Interstitial / metabolism
  • Lung Diseases, Interstitial / pathology
  • Phospholipids / metabolism
  • Phospholipids / pharmacology
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / physiology*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / physiology


  • ABCA3 protein, human
  • ATP-Binding Cassette Transporters
  • Phospholipids
  • Cholesterol