Sirtuin 6 ameliorates bleomycin-induced pulmonary fibrosis via activation of lipid catabolism

J Cell Physiol. 2024 Mar;239(3):e31027. doi: 10.1002/jcp.31027. Epub 2023 Apr 26.

Abstract

Pulmonary fibrosis is a chronic and serious interstitial lung disease with little effective therapies currently. Our incomplete understanding of its pathogenesis remains obstacles in therapeutic developments. Sirtuin 6 (SIRT6) has been shown to mitigate multiple organic fibrosis. However, the involvement of SIRT6-mediated metabolic regulation in pulmonary fibrosis remains unclear. Here, we demonstrated that SIRT6 was predominantly expressed in alveolar epithelial cells in human lung tissues by using a single-cell sequencing database. We showed that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells in vitro and pulmonary fibrosis of mice in vivo. High-throughput sequencing revealed enriched lipid catabolism in Sirt6 overexpressed lung tissues. Mechanismly, SIRT6 ameliorates bleomycin-induced ectopic lipotoxicity by enhancing lipid degradation, thereby increasing the energy supply and reducing the levels of lipid peroxides. Furthermore, we found that peroxisome proliferator-activated receptor α (PPARα) was essential for SIRT6-mediated lipid catabolism, anti-inflammatory responses, and antifibrotic signaling. Our data suggest that targeting SIRT6-PPARα-mediated lipid catabolism could be a potential therapeutic strategy for diseases complicated with pulmonary fibrosis.

Keywords: Sirtuin 6; bleomycin; lipid catabolism; peroxisome proliferator-activated receptor α; pulmonary fibrosis.

MeSH terms

  • Animals
  • Bleomycin
  • Humans
  • Lipid Metabolism*
  • Mice
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Pulmonary Fibrosis* / chemically induced
  • Pulmonary Fibrosis* / genetics
  • Pulmonary Fibrosis* / metabolism
  • Sirtuins* / genetics
  • Sirtuins* / metabolism

Substances

  • Bleomycin
  • PPAR alpha
  • SIRT6 protein, human
  • Sirtuins