Increased expression of the glucose transporter GLUT1 in liver fibrosis

The activation of hepatic stellate cells (HSC) is a key event of hepatic fibrosis. Hyperglycemia is one of the factors known to induce and promote hepatic fibrogenesis, however, mechanisms regulating glucose uptake into HSC have not been studied so far. Normal liver reveals only low expression of the facilitative glucose transporter (GLUT) 1, but its expression is increased in hepatocellular carcinoma (HCC), where GLUT1 has been shown to be a tumor promotor.

The aim of this study was to assess GLUT1 expression in liver fibrosis.

Methods and Results: Hepatic GLUT1 expression was significantly increased in the bile-duct-ligation model, the CCl4-model and a dietary NASH-model in mice as well as in human liver samples with cirrhosis or NAFLD of various degree. GLUT1 expression revealed a significant correlation with collagen I and alpha-sma levels indicating activated HSC as cellular source of GLUT1, which was confirmed by immunohistochemistry. 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 the 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.

Conclusions: Increased GLUT1 expression during HSC activation and further induction via hypoxia, which is a known pathophysiological factor in diseased livers, may functionally promote 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.