Pgc-1 Alpha Regulates Autophagy To Promote Fibroblast Activation And Tissue Fibrosis

Objectives Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) in the pathogenesis of systemic sclerosis (SSc).Methods Expression of PGC-1 alpha was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1 alpha knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1 alpha.Results The expression of PGC-1 alpha was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGF beta), hypoxia and epigenetic mechanisms regulate the expression of PGC-1 alpha in fibroblasts. Knockdown of PGC-1 alpha prevented the activation of autophagy by TGF beta and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1 alpha in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGF beta receptor type I. Moreover, pharmacological inhibition of PGC-1 alpha by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis.Conclusion PGC-1 alpha is upregulated in SSc and promotes autophagy to foster TGF beta-induced fibroblast activation. Targeting of PGC-1 alpha prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.