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Abstract
BackgroundFour and one half LIM domain protein 2 (FHL2) has been reported to be a key regulator in many cellular processes being associated with fibrogenesis such as cell migration and contraction. Moreover, hepatic FHL2 is involved in regulation pathways mediating proliferation and cell death machineries. We here investigated the role of FHL2 in the setting of experimental and clinical liver fibrosis.MethodsFHL2−/− and wild type (wt) mice were challenged with CCl4. Fibrotic response was assessed by quantitative real time PCR (qRT-PCR) of fibrotic marker genes, measurement of hydroxyproline content and histological methods. Murine FHL2−/− and hepatic stellate cells (HSC) were isolated and investigated via immunofluorescence. Human fibrotic and normal liver samples were analysed immunohistochemically using antibodies directed against FHL2.ResultsFHL2−/− mice displayed aggravated liver fibrosis compared to wt mice. However, immunofluorescence revealed no significant morphological changes in cultured FHL2−/− and wt myofibroblasts (MFB). In human liver samples, FHL2 was strongly expressed both in the nucleus and cytoplasm in MFB of fibrotic livers. In contrast, FHL2 expression was absent in normal liver tissue.ConclusionsDeficiency of FHL2 results in aggravation of murine liver fibrosis. In human liver samples, FHL2 is expressed in activated HSCs and portal fibroblasts in human fibrotic livers, pointing to a central role of FHL2 for human hepatic fibrogenesis as well.
Highlights
Four and one half LIM domain protein 2 (FHL2) has been reported to be a key regulator in many cellular processes being associated with fibrogenesis such as cell migration and contraction
FHL2−/− mice developed significantly aggravated liver fibrosis compared to respective wt control mice as demonstrated in Sirius Red stain (Figure 2A-2D)
This study shows for the first time that FHL2 is crucial in experimental liver fibrosis
Summary
Four and one half LIM domain protein 2 (FHL2) has been reported to be a key regulator in many cellular processes being associated with fibrogenesis such as cell migration and contraction. Murine FHL2−/− and hepatic stellate cells (HSC) were isolated and investigated via immunofluorescence. Human fibrotic and normal liver samples were analysed immunohistochemically using antibodies directed against FHL2. Immunofluorescence revealed no significant morphological changes in cultured FHL2−/− and wt myofibroblasts (MFB). FHL2 was strongly expressed both in the nucleus and cytoplasm in MFB of fibrotic livers. Liver fibrosis is characterized by a significant increase of collagenous matrix. Myofibroblastic activated HSC represent the key fibrogenic cells in the liver. Besides the production of extracellular matrix, these cells show increased proliferation, migration and contraction. FHL2 belongs to the superfamily of LIM domain proteins, which harbour a common zinc finger domain allowing flexible protein-protein interaction [2,3]
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