Increased expression of the Glucose-transporter GLUT1 during hepatic stellate cell activation promotes hepatic fibrosis

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. Furthermore, these cells form and transduce the HCC stroma.

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. To gain insight in the functional role of GLUT1 in activated HSCs we inhibited GLUT1 expression with siRNA or the specific GLUT1 inhibitor WZB117 and found 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. Transgenic GLUT1 knockdown mice subjected to TAA induced liver fibrosis model revealed less pronounced liver damage than WT animals confirmed by hepatic sirius red staining and alpha-sma protein expression. In line with this, treatment with GLUT1 inhibitor WZB117 in combination with the NASH inducing MCD diet resulted in less hepatic alpha-sma and collagen I expression than animals treated with vehicle.

Conclusions: Increased GLUT1 expression during HSC activation 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.

Corresponding author: Czech, Barbara

E-Mail: barbara.czech@ukr.de