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  • Mammals have three known Gli proteins Gli and Gli does

    2022-08-05

    Mammals have three known Gli proteins: Gli-1, -2 and -3. Gli-1 does not undergo proteosomal degradation and hence, remains untruncated and always acts as a transcription promoter. Gli-1 is an important target gene for Gli-2. Full-length Gli-2 accumulates when Smo is activated because activated Smo protects Gli-2 from proteosomal degradation. When Smo is inactive, both Gli-2 and Gli-3 are targeted to the proteasome; Gli-2 is usually fully degraded but Gli-3 is frequently partially processed to a truncated form that acts as a transcriptional repressor. As such, Gli-3 can act as either a transcriptional repressor (when Smo is inactive) or as an activator of transcription (when activated Smo protects it from proteosomal degradation). In contrast, Gli-1 and Gli-2 act predominantly as transcriptional promoters (Table 1). Besides the canonical Hh pathway, there are also two known types of non-canonical Hh signalling. Type 1 non-canonical Hh signalling depends on Patch but is Smo-independent. In the absence of Hh, Patch has direct pro-apoptotic and anti-proliferative effects, by activating caspase-3 and preventing nuclear localisation of cyclin D, respectively. Both effects of Patch are lost when Hh binds to Patch. Type 2 non-canonical Hh signalling depends on Smo but it does not require PC. This non-canonical signalling depends on the Giα activity of Smo that directly regulates metabolism (for example it promotes a Warburg-like effect promoting glycolysis in muscle, adipose tissue and myofibroblasts[30], [31]), proliferation, calcium flux and migration (in myofibroblasts and endothelial cells[32], [33], [34]), in a Gli-independent mechanism. Additionally, Gli signalling can occur in the absence of Hh via a process that also appears to be Patch- and Smo-independent, as demonstrated by evidence that Gli induction is a direct downstream consequence of transforming growth factor (TGF) beta and RAS signalling.[35], [36], [37]
    The hedgehog pathway in the liver Hepatic Development: The role of Hh in the embryogenesis of the liver is not fully understood. Shh is strongly expressed in the ventral foregut endoderm which gives rise to the liver, pancreas and lung buds. Shh expression disappears as the liver bud forms,[38], [39] but it is transiently induced in hepatoblasts later in development. As hepatoblasts differentiate into hepatocytes, Shh expression is reduced again, suggesting that Shh is necessary to generate, maintain, and expand certain populations of liver progenitors, but must be inhibited for these Epalrestat to differentiate into mature liver epithelial cells. Healthy Adult Liver: In healthy adult liver, the Hh pathway is relatively dormant due to both very low production of ligands by liver-resident cells (e.g. occasional immature-appearing cholangiocytes), and robust expression of Hh inhibitors, Epalrestat such as Hhip, by quiescent HSC. Interestingly, emerging evidence suggests that this low level of pathway activity may fluctuate in a circadian fashion and help to regulate zonal differences in hepatic metabolism by modulating the relative levels of various Gli factors in hepatocytes.[41], [42] These recent observations raise the intriguing possibility that mammalian liver may be exposed (and respond) to Hh ligands derived from extra-hepatic sources. In flies, for example, Hh ligand is produced by intestinal epithelial cells and carried in lipoproteins to the fat body (an organ with dual adipose- and liver-like functions) where it has metabolic activity. Hh inhibits lipogenesis in both flies and mammals.[22], [44] Hh ligands have been demonstrated in human lipoproteins, but the source(s) of lipoprotein-associated Hh ligands and their function in man are unknown. This issue merits further study given recent evidence that inherited Smo defects, which abrogate Hh signalling in humans, lead to hepatic steatosis. Injured Adult Liver: Hh ligand expression is induced in liver-resident cells and robust Hh pathway activity reemerges in adults in response to situations that trigger acute liver regeneration (e.g. after an acute liver insult with hepatic necrosis or after partial hepatectomy) or chronic liver regeneration/repair (e.g. all types of chronic liver injury). Indeed, the level of Hh pathway activation generally correlates with the severity and duration of the liver injury, regardless of aetiology. The fact that Hh pathway activity closely parallels the intensity of the regenerative stimulus probably reflects the fact that the production of Hh ligands is stimulated by several factors that accumulate in injured livers, including platelet derived growth factor (PDGF), TGF-β, and epidermal growth factor (EGF).[48], [49], [50] During liver wound healing, various liver-resident cell types produce Shh and/or Ihh ligands, including injured/dying hepatocytes (e.g. ballooned hepatocytes in steatohepatitis), injured/activated cholangiocytes (e.g. in ductular reactions and cholangiopathies), myofibroblastic stellate cells (e.g. during fibrogenesis), sinusoidal endothelial cells (e.g. during capillarisation), and immune cells (e.g. macrophages and NKT cells during fibrogenesis).[40], [48], [51], [52], [53], [54], [55], [56], [57], [58] Further, local production of Hh inhibitors is reduced as HSCs quickly suppress their production of Hhip when they are becoming myofibroblastic.[53], [54] These reciprocal changes in local production of Hh ligands and Hh inhibitors generate a microenvironment that promotes Hh pathway activation in Hh-responsive target cells (Fig. 2).