Research ArticleFibrosis

Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β

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Science Signaling  17 Dec 2019:
Vol. 12, Issue 612, eaax4067
DOI: 10.1126/scisignal.aax4067

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Glycolysis promotes lung fibrosis

Transforming growth factor–β (TGF-β) promotes fibrosis by stimulating fibroblasts to proliferate and differentiate into matrix-secreting myofibroblasts. Yin et al. found that the glycolytic enzyme hexokinase 2 (HK2) was highly abundant in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and that TGF-β induced the accumulation of HK2 and stimulated glycolysis in mouse and human lung fibroblasts. Pharmacological inhibition of HK2 with Lonidamine attenuated the profibrotic actions of TGF-β in fibroblasts. Lonidamine also reduced molecular markers of fibrosis and improved lung function in a mouse model of lung fibrosis. Thus, HK2-dependent metabolic dysregulation contributes to lung fibrosis and is a potential therapeutic target.

Abstract

Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor–β (TGF-β). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-β both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-β signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-β–stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability. Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibited an increased abundance of HK2. In a mouse model of bleomycin-induced lung fibrosis, Lonidamine reduced the expression of genes encoding profibrotic markers (collagenΙα1, EDA-fibronectin, α smooth muscle actin, and connective tissue growth factor) and stabilized or improved lung function as assessed by measurement of peripheral blood oxygenation. These findings provide evidence of how metabolic dysregulation through HK2 can be integrated within the context of profibrotic TGF-β signaling.

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