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Review
, 14 (12), 1636-1644
eCollection

Role of Canonical Hedgehog Signaling Pathway in Liver

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Review

Role of Canonical Hedgehog Signaling Pathway in Liver

Lili Gao et al. Int J Biol Sci.

Abstract

Hedgehog (Hh) signaling pathway plays an important role in embryonic development. It becomes reactivated in many types of acute and chronic liver injuries. Hh signaling is required for liver regeneration, regulates capillarisation, controls the fates of hepatic stellate cells, promotes liver fibrosis and liver cancers. In this review, we summarize the current knowledge of the role of canonical Hh signaling pathway in adult liver. This help to understand the pathogenesis of liver diseases and find out the new effective targeted therapeutic strategies for liver diseases treatments.

Keywords: HCC; Hedgehog; fibrosis; liver.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Hh signaling pathway in vertebrate. (A) In the absence of Hh ligands, low levels of PI(4)P intact with Ptch. Ptch represses Smo activity by preventing its accumulation within cilia. Smo associates with SENP family members leading to its ubiquitination and degradation. Glis associate with SuFu and Kif7 to form the complex in the cytoplasm associated with microtubules. PKA, Cklα and Gsk3β promote phosphorylation of Glis to suppress their transcriptional activity (GliR). (B) In the presence of Hh ligands, inhibition of Smo by Ptch was relieved, leading to the translocation and accumulation of Smo at cilia. PI(4)P directly binds Smo which then triggers Smo phosphorylation. Sumoylation and cholesterol modification on D95 are also required for Hh signaling pathway activation. Glis dissociate the SuFu-Gli complex. Glis were in their active forms (GliA). GliA enters into the nucleus to regulate gene expression.
Figure 2
Figure 2
Hh signaling in required for liver regeneration post-PH. (A) In adult healthy liver, hepatocytes barely expressed Hh ligand. Bile ductular cells and hepatic stellate cells express Hh ligands, and have endogenous Hh pathway activity. (B) a) Hh pathway is activated in hepatocytes and bile ductular cells post-PH. b) Hh pathway is activated in hepatic stellate cells post-PH. Hh signaling promotes transition of quiescent hepatic stellate cells to myofibroblast. Some of myofibroblasts become progenitors that regenerate the liver epithelial compartment after PH. c) Hh signaling promotes progenitor cell accumulation post-PH.
Figure 3
Figure 3
Hh signaling regulates the activation and viability of hepatic stellate cells and promotes liver fibrosis. Active hepatic stellate cells secrete fibrillar collagens, induce robust induction of α-SMA, matrix molecules, matrix metalloproteinases, and express tissue inhibitors of metalloproteinases, resulting in the accumulation of fibrotic extracellular matrix. Some of myofibroblasts can become multipotent progenitors to regenerate hepatocytes, cholangiocytes, and hepatic stellate cells. Blocking Hh signaling in myofibroblasts not only inhibited liver fibrosis but also prevented accumulation of liver progenitors.
Figure 4
Figure 4
Activation of Hh signaling in hepatocytes and NKT cells promotes OPN production. (A) Activation of Hh signaling in hepatocytes increases the production of OPN, which subsequently enhanced the macrophage-mediated proinflammatory response. (B) Activation of Hh signaling in NKT cells associates OPN promotes HSC activation and liver fibrogenesis.

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