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

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.

Metabolic reprogramming: A driver of cigarette smoke-induced inflammatory lung diseases

“…Furthermore, glutaminolysis, the process of metabolizing glutamine into glutamate, was enhanced by TGF-β1 by inducing glutaminase 1 expression in lung myofibroblasts [87,88]. This process, as a result, facilitated fibroblast differentiation and collagen production [86][87][88].…”

“…Upon recognition of metabolic dysregulation in IPF, the transforming growth factor beta (TGF-β), a potent inducer of fibrosis, was found to influence metabolic pathways for promoting myofibroblast differentiation and their functions [85]. The expression of hexokinase isoform, hexokinase 2 (HK2), which phosphorylates glucose into glucose-6-phosphate, was higher in IPF lung fibroblasts to aid TGF-β mediated profibrotic events [86] (Fig. 2).…”

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

“…Other direct targets of TGF-β1 include the glycolytic enzymes phosphofructokinase (PFK) (Calvier et al, 2017) and hexokinase (Yin et al, 2019) which catalyze key regulatory steps in the conversion of glucose to pyruvate.…”

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

“…For example, hypoxiainducible factor 1α (HIF-1α) binds the promoter of HK2 to activate HK2 transcription, which accelerates glycolysis and facilitates cutaneous squamous cell carcinoma (cSCC) development (Zhou et al, 2018). In addition, the expression of HK2 is activated by transforming growth factor-β (TGF-β) and this activation requires transcription factors like Smad2, Smad3, and c-Myc (Yin et al, 2019).…”