Lipid synthesis is required to resolve endoplasmic reticulum stress and limit fibrotic responses in the lung

Freddy Romero, Xu Hong, Dilip Shah, Caleb B. Kallen, Ivan Rosas, Zhi Guo, De Leila Schriner, Julie Barta, Hoora Shaghaghi, Jan B. Hoek, Clementina Mesaros, Augustine M. Choi, Nathaniel W. Snyder, Ross Summer

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Endoplasmic reticulum (ER) stress is evident in the alveolar epithelium of humans and mice with pulmonary fibrosis, but neither the mechanisms causing ER stress nor the contribution of ER stress to fibrosis is understood. A well-recognized adaptive response to ER stress is that affected cells induce lipid synthesis; however, we recently reported that lipid synthesis was downregulated in the alveolar epithelium in pulmonary fibrosis. In the present study, we sought to determine whether lipid synthesis is needed to resolve ER stress and limit fibrotic remodeling in the lung. Pharmacologic and genetic manipulations were performed to assess whether lipid production is required for resolving ER stress and limiting fibrotic responses in cultured alveolar epithelial cells and whole-lung tissues. Concentrations of ER stress markers and lipid synthesis enzymes were also measured in control and idiopathic pulmonary fibrosis lung tissues. We found that chemical agents that induce ER stress (tunicamycin or thapsigargin) enhanced lipid production in cultured alveolar epithelial cells and in the mouse lung. Moreover, lipid production was found to be dependent on the enzyme stearoyl–coenzyme A desaturase 1, and when pharmacologically inhibited, ER stress persisted and lung fibrosis ensued. Conversely, lipid production was reduced in mouse and human fibrotic lung, despite there being an increase in the magnitude of ER stress. Furthermore, augmenting lipid production effectively reduced ER stress and mitigated fibrotic remodeling in the mouse lung after exposure to silica. Augmenting lipid production reduces ER stress and attenuates fibrotic remodeling in the mouse lung, suggesting that similar approaches might be effective for treating human fibrotic lung diseases.

Original languageEnglish (US)
Pages (from-to)225-236
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume59
Issue number2
DOIs
StatePublished - Aug 2018

Keywords

  • Alveolar epithelium
  • Endoplasmic reticulum stress
  • Lipid synthesis
  • Pulmonary fibrosis
  • Unfolded protein response

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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