Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

Abstract

Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)-induced glycolysis regulates age-dependent fibrogenesis of the lung. Mouse and human lung tissues were analyzed for GLUT1 and glycolytic markers using immunoblotting. Glycolytic function was measured using a Seahorse apparatus. To study the effect of GLUT1, genetic inhibition of GLUT1 was performed by short hairpin RNA transduction, and phloretin was used for pharmacologic inhibition of GLUT1. GLUT1-dependent glycolysis is activated in aged lung. Genetic and pharmacologic inhibition of GLUT1 suppressed the protein expression of a-smooth muscle actin, a key cytoskeletal component of activated fibroblasts, in mouse primary lung fibroblast cells. Moreover, we demonstrated that the activation of AMPactivated protein kinase, which is regulated by GLUT1-dependent glycolysis, represents a critical metabolic pathway for fibroblast activation. Furthermore, we demonstrated that phloretin, a potent inhibitor of GLUT1, significantly inhibited bleomycin-induced lung fibrosis in vivo. These results suggest that GLUT1-dependent glycolysis regulates fibrogenesis in aged lung and that inhibition of GLUT1 provides a potential target of therapy of age-related lung fibrosis.

Glucolipotoxicity: A Proposed Etiology for Wooden Breast and Related Myopathies in Commercial Broiler Chickens

“…The greater role of insulinindependent glucose transport in cardiac and smooth muscle allows glucose uptake even when glycolysis and glycogenesis are impaired. The importance of insulin-insensitive glucose transport in development of diabetic retinopathy (Kumagai, 1999), atherosclerosis (Wall et al, 2018), diabetic nephropathy (Brosius and Heilig, 2005), pulmonary fibrosis (Cho et al, 2017), diabetic myocardial fibrosis (Asbun and Villarreal, 2006;Gorski et al, 2019) and non-alcoholic fatty liver disease (Nanji et al, 1995) has been demonstrated and is in support of our hypothesis that wooden breast shares substantial etiological factors with type 2 diabetes in mammals.…”

Assessment of 18F-FDG uptake in idiopathic pulmonary fibrosis: influence of lung density changes

“…Activated fibroblasts have an increased metabolic activity with increased glucose consumption and glycolysis (Xie et al, 2015). Studies also revealed an increased expression of the glucose transporter 1 (GLUT-1) in fibroblasts from IPF patients as well as in epithelial cells and inflammatory cells (El-Chemaly et al, 2013;Cho et al, 2017;Andrianifahanana et al, 2016). Interestingly, GLUT-1 is the main transporter of glucose and [18F]-FDG (El-Chemaly et al, 2013).…”

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

“…18,20,35 Xiong et al also showed that isoform switch from PKM1 to PKM2 is required for a pro-glycolytic phenotype in the cardiac biventricular pressure overload model of Group 2 PH. 18,20,35 Xiong et al also showed that isoform switch from PKM1 to PKM2 is required for a pro-glycolytic phenotype in the cardiac biventricular pressure overload model of Group 2 PH.…”

“…One such experiment is transverse aortic constriction (TAC) where chronic pressure overload enhances glycolytic activity [10][11][12] and fibrosis 13,14 of the left ventricle (LV). 16 Glycolysis is a multiple step metabolic process in response to glucose uptake 17,18 in which enzymatically catalyzed steps convert glucose to pyruvate molecules for cellular energy generation. Likewise, we also examined the in vivo influence of hyperglycemia on TG2 expression and activity in type 1 diabetic Akita mice with elevated blood glucose levels.…”