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DOI: 10.1055/s-0034-1397060
Functional effects of monocarboxylate transporter 1 expression in activated hepatic stellate cells
Monocarboxylate transporter 1 (MCT1) belongs to the SLC16 transporter gene family. MCT1 is involved in the transmembrane transport of lactic acid and other monocarboxylic acids in healthy tissue. Furthermore, it has been recognized that MCT1 contributes to the maintenance of the metabolic phenotype of tumor cells but the role of MCT1 in liver disease is unknown.
The aim of this study was to assess the expression and function of MCT1 and its chaperone CD147 (basigin), a transmembrane protein that is responsible for targeting MCT1 to the cell membrane, in hepatic fibrosis.
Methods and Results: Quantitative PCR and western blot analysis revealed significantly increased hepatic MCT1 and CD147 expression 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 human NASH and cirrhotic liver tissue MCT1 and CD147 expression were increased compared to normal liver tissue. Immunohistochemical analysis showed strong MCT1 and CD147 staining in fibrotic septa, and coimmunofluorescence analysis with alpha-smooth muscle actin, a specific marker for activated hepatic stellate cells (HSCs) revealed strong expression of MCT1 and CD147 in these cells. In line with this, we found that MCT1 and CD147 expression increased during in vitro activation of primary murine and human HSCs. Hypoxia, a pathological factor known to promote hepatic fibrosis, further increased MCT1 and CD147 expression in activated HSCs in vitro. Also secretion of lactate increased time dependently during in vitro activation of HSCs and was further increased by hypoxia. In contrast, inhibition of MCT1 led to a significant reduction of lactate secretion in HSCs. Stimulation with exogenous lactate dose dependently induced proliferation of activated HSCs. Furthermore, lactate induced increased activation of NFkappaB and expression of NFkappaB regulated proinflammatory genes such as MCP-1 in activated HSCs.
Conclusions: Our study identified MCT1 and likely also its chaperone CD147 as regulators of autocrine lactate secretion of HSCs and herewith also as critical mediators of the profibrogenic phenotype of HSCs. Strong expression in contrast to other liver cell types favors MCT1 and its chaperone as targets for antifibrogenic therapy in chronic liver disease.
Corresponding author: Czech, Barbara
E-Mail: barbara.czech@ukr.de