Expression and function of glucose transporter 1 (GLUT1) expression in activated hepatic stellate cells

Hyperglycemia is one of the factors known to induce and promote hepatic fibrogenesis, however, glucose metabolism in activated hepatic stellate cells (HSCs), the key cells in hepatic fibrosis, is unknown. Aerobic glycolysis despite the presence of oxygen is a characteristic of tumor cells. Thus, glucose transporter 1 (GLUT1) is highly expressed in hepatocellular carcinoma (HCC), where GLUT1 acts as a tumor promoter, while normal liver expresses only low levels of GLUT1. Furthermore, the expression of monocarboxylate transporters (MCTs), which are responsible for lactate transport, is characteristic for the glycolytic switch in tumor cells.

The aim of this study was to assess the expression of GLUT1, MCTs and their chaperons CD147 (basigin) and GP70 (embigin) in liver fibrosis.

Methods and Results: Hepatic GLUT1 and MCT1 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 and MCT1 expression was increased. Interestingly, immunohistochemical staining revealed strong expression of these transporters in activated HSCs in fibrotic liver tissues. In line with this, we found that GLUT1, MCT1 and MCT4 expression increased during in vitro activation of primary murine and human HSCs. Hypoxia led to a further increase of the expression of GLUT1, MCT1 and its chaperones CD147 and GP70. In contrast and interestingly, MCT4 expression was downregulated in activated HSC under hypoxia. To gain insight into the functional role of GLUT1 in activated HSCs we inhibited GLUT1 expression with siRNA 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. Moreover, GLUT1 suppression impaired the expression of MCT1 and MCT4 as well as CD147 and GP70.

Conclusions: GLUT1 affect glucose metabolisms and expression of lactate transporters in HSCs. Enhanced expression of these transporters during HSCs activation is further induced via hypoxia, which is a known pro-fibrogenic 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.