Effect of increased glucose transporter 1 (GLUT1) expression in activated hepatic stellate cells

Normal liver reveals only low expression of the facilitative glucose transporter (GLUT) 1. Recently, we have shown that GLUT1 expression is increased in hepatocellular carcinoma (HCC), where GLUT1 acts as a tumor promotor. Hyperglycemia is one of the factors known to induce and promote hepatic fibrogenesis, and the activation of hepatic stellate cells (HSCs) is the key event of hepatic fibrosis.

The aim of this study was to assess the expression and functional role of GLUT1 in hepatic fibrosis.

Methods and Results: Hepatic GLUT1 expression was significantly increased in different murine models of hepatic fibrosis, namely chronic TAA or CCl4-application, bile-duct-ligation and dietary models of non-alcoholic steatohepatitis (NASH). Also in cirrhotic human livers and human NASH GLUT1 expression was increased. Interestingly, hepatic GLUT1 expression revealed a significant correlation with collagen I and alpha-sma levels indicating activated HSCs as cellular source of GLUT1, which was confirmed by immunohistochemical analysis. In line with this, we found that GLUT1 expression increased during in vitro activation of primary murine and human HSCs. Chemically and physically induced hypoxia led to a further increase of GLUT1 expression in activated HSC. The rapid time course and the inhibitory effect of actinomycin D on hypoxia induced GLUT1 expression indicated a regulation on the transcriptional level. In line with this, pre-incubation with chemical inhibitors of the transcription factor HIF1alpha significantly reduced both basal as well as hypoxia induced GLUT1 expression in activated HSCs. To gain insight in the functional role of GLUT1 in activated HSCs we inhibited GLUT1 expression with siRNA and we could show that GLUT1 suppression impaired Glucose uptake and lactate secretion of HSCs indicative for reduced anaerobic glycolysis. Functional analysis demonstrated that reduced GLUT1 expression led to lower apoptosis resistance of HSCs.

Conclusions: Increased GLUT1 expression during HSC activation and further induction via hypoxia, which is a known pathophysiological factor in diseased livers, functionally affects HSCs, and herewith, likely promotes the development and progression of hepatic fibrosis. Therefore and based on its known role as tumor-promotor, GLUT1 appears as attractive novel target to inhibit the progression of chronic liver disease.