The Regulation of Fatty Acid Synthase by Exosomal miR-143-5p and miR-342-5p in Idiopathic Pulmonary Fibrosis

Hassan Hayek, Ohoud Rehbini, Beata Kosmider, Thomas Brandt, Wissam Chatila, Nathaniel Marchetti, Gerard J Criner, Sudhir Bolla, Raj Kishore, Russell P Bowler, Karim Bahmed

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease caused by an aberrant repair of injured alveolar epithelial cells. The maintenance of the alveolar epithelium and its regeneration after the damage is fueled by alveolar type II (ATII) cells. Injured cells release exosomes containing miRNAs, which can alter the recipient cells' function. Lung tissue, ATII cells, fibroblasts, plasma, and exosomes were obtained from naïve IPF and IPF patients taking pirfenidone and nintedanib and organ donors. MiRNAs expression was analyzed to study their impact on exosome-mediated effects in IPF. High miR-143-5p and miR-342-5p levels were detected in ATII cells, lung tissue, plasma, and exosomes in naïve IPF. Decreased FASN and ACSL-4 expression was found in ATII cells. MiR-143-5p and miR-342-5p overexpression or ATII cell treatment with IPF-derived exosomes containing these miRNAs lowered FASN and ACSL-4 levels. Also, this contributed to ATII cell injury and senescence. However, exosomes isolated from IPF patients taking nintedanib or pirfenidone increased FASN expression in ATII cells compared to naïve IPF. Furthermore, fibroblast treatment with exosomes obtained from naïve IPF increased SMAD3, CTGF, COL3A1, and TGFβ1 expression. Our results suggest that IPF-derived exosomes containing miR-143-5p and miR-342-5p inhibited the de novo fatty acid synthesis pathway in ATII cells. They also induced the pro-fibrotic response in fibroblasts. Pirfenidone and nintedanib improved ATII cell function and inhibited fibrogenesis. This study highlights the importance of exosomes in IPF pathophysiology.

Original languageEnglish
Pages (from-to)259-282
Number of pages24
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume70
Issue number4
Early online dateNov 20 2023
DOIs
StatePublished - Apr 1 2024

Keywords

  • IPF
  • alveolar type II cells
  • exosomes
  • fatty acid synthesis
  • microRNA
  • Lung/metabolism
  • MicroRNAs/genetics
  • Idiopathic Pulmonary Fibrosis/metabolism
  • Fatty Acid Synthases/metabolism
  • Humans
  • Exosomes/metabolism
  • Alveolar Epithelial Cells/metabolism

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