Key result
FHL2 deficiency aggravates liver fibrosis in mice, indicating a protective role in hepatic fibrogenesis.
FHL2 deficiency aggravates murine liver fibrosis, and FHL2 is upregulated in activated hepatic stellate cells in human fibrotic livers, suggesting a central role in hepatic fibrogenesis.
FHL2 modulation should not yet alter clinical fibrosis management; leaves open its role as a therapeutic target in human hepatic fibrogenesis.
BACKGROUND: 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. 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. METHODS: FHL2(-/-) and wild type (wt) mice were challenged with CCl(4). 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. RESULTS: FHL2(-/-) 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. CONCLUSIONS: Deficiency 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.
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Huss et al. (2013) studied Liver fibrosis (n=29). FHL2 deficiency vs. Wild-type mice was evaluated on Liver fibrosis severity (collagen deposition and hepatic hydroxyproline content). FHL2-deficient mice displayed significantly aggravated liver fibrosis compared to wild-type mice after CCl4 challenge, indicating a protective role of FHL2 in hepatic fibrogenesis.
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