Idiopathic pulmonary fibrosis (IPF) is a chronic human disease with persistent destruction of lung parenchyma. A pivotal role in the initiation and pathogenesis of IPF is played by transforming growth factor (TGF)-β1 signaling. As shown herein, TGF-β1 signaling down-regulates not only peroxisome biogenesis but also the metabolism of these organelles in human IPF fibroblasts. In accordance with the in vitro cell culture observations in human fibroblasts and human lung tissue, peroxisomal biogenesis and metabolic proteins were significantly down-regulated in the lung of 1-month-old transgenic mice expressing a constitutively active TGF-β type I receptor (ALK5). In the opposite direction, the peroxisome biogenesis protein PEX13p as well as the peroxisomal lipid metabolic enzyme ACOX1 and antioxidative enzyme catalase were enormously up-regulated in TGF-β type II receptor and Smad3 knockout mice. A novel mechanism of peroxisome biogenesis and metabolic regulation via TGF-β1-Smad signaling is reported in this study: by demonstrating the interaction of the Smad3 transcription factor with the PEX13 gene in chromatin immunoprecipitation-on-chip assay as well as in a bleomycin-induced pulmonary fibrosis model applied to TGF-β type II receptor knockout mice. Taken together, TGF-β1 participates in regulation of peroxisomal biogenesis and metabolism via Smad-dependent signaling, opening novel strategies for the development of therapeutic approaches that might inhibit pulmonary fibrosis progression in patients with IPF.
- Oruqaj, G.
- Karnati, S.
- Kotarkonda, L. K.
- Boateng, E.
- Bartkuhn, M.
- Zhang, W.
- Ruppert, C.
- Günther, A.
- Bartholin, L.
- Shi, W.
- Baumgart-Vogt, E.