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6 Pdfsam
6 Pdfsam
6 Pdfsam
transcription of fibrillar collagen and α-smooth muscle actin (α-SMA), leading to formation
contact (Higashi et al., 2017; Puche et al., 2014). Thus, elucidating the molecular
mechanisms that trigger HSC activation is the most important part of regulating fibrotic
responses.
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The TGF-β1/Smad signaling is known to play a critical role in activation of HSCs and
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regulation of the production and accumulation of ECM proteins (Fabregat et al., 2016). The
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onset of TGF-β1/Smad signaling occurs when TGF-β binds to the serine/threonine kinase
receptor, TβRII, phosphorylating its transducer receptor, TβRI. The activated TβRI then
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recruits and phosphorylates R-Smads (Smad2/3), which are transcription factors that typically
bind co-Smad (Smad4), after which these R-Smad complexes accumulate in the cell nucleus,
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where they increase the transcriptional level of specific target genes (e.g., collagen-I) (Inagaki
Recent studies suggested that the Hippo pathway and its downstream effector, Yes-
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associated protein (YAP), act as critical regulators of HSC activation (Mannaerts et al., 2015).
In recent studies, YAP was found to be elevated in the nucleus through HSC activation and
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the inhibition of YAP prevented early HSC activation in vitro as well as the overall processes
of fibrogenesis in vivo (Mannaerts et al., 2015). Therefore, the present study investigated the
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associated with HSCs activation using an in vivo mouse model of liver fibrosis induced by
carbon tetrachloride (CCl4) and an in vitro model based on LX-2 cells treated with or without
TGF-β1.