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Review
. 2018 Mar;68(3):550-562.
doi: 10.1016/j.jhep.2017.10.017. Epub 2017 Oct 26.

Hedgehog signalling in liver pathophysiology

Mariana Verdelho Machado  1 , Anna Mae Diehl  2
Affiliations
Review

Hedgehog signalling in liver pathophysiology

Mariana Verdelho Machado et al. J Hepatol. 2018 Mar.

Abstract

Liver disease remains a leading cause of mortality worldwide despite recent successes in the field of viral hepatitis, because increases in alcohol consumption and obesity are fuelling an epidemic of chronic fatty liver disease for which there are currently no effective medical therapies. About 20% of individuals with chronic liver injury ultimately develop end-stage liver disease due to cirrhosis. Hence, treatments to prevent and reverse cirrhosis in individuals with ongoing liver injury are desperately needed. The development of successful treatments requires an improved understanding of the mechanisms controlling liver disease progression. The liver responds to diverse insults with a conserved wound healing response, suggesting that it might be generally beneficial to optimise pathways that are crucial for effective liver repair. The Hedgehog pathway has emerged as a potential target based on compelling preclinical and clinical data, which demonstrate that it critically regulates the liver's response to injury. Herein, we will summarise evidence of the Hedgehog pathway's role in liver disease and discuss how modulating pathway activity might be applied to improve liver disease outcomes.

Keywords: Hedgehog pathway; Liver disease; Wound healing response.

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Figures

Figure 1
Figure 1. The simplified representation of the Hedgehog signaling pathway
A. In the absence of Hedgehog ligand (Hh), Patched (Patch) prevents Smoothened (Smo) from entering the primary cilium (PC), repressing Smo activity. This allows the sequential phosphorylation of Gli by several kinases: protein kinase A (PKA), glycogen synthase-3β(GSK3β) and casein kinase-1 (CK1). Phosphorylated Gli is susceptible for ubiquitination by Skip-Cullin-F-box (SCF) protein/β-Transducing repeat Containing Protein (TrCP), which primes Gli to limited degradation in the proteasome. Truncated Gli (Gli-R) acts as a repressor of gene transcription. B. When hedgehog binds to Patch, it removes Patch from the PC, allowing Smo to enter the PC. The complex Hh-Patch is degraded in vesicles in the cytoplasm. The entry of Smo into the PC allows Smo activation. Active Smo abrogates phosphorylation and subsequent degradation of Gli. Full length Gli translocates to the nucleus where it acts as a transcription factor for several target genes. Of note, Shh, Ihh and Dhh ligands similarly activate the Hh pathway. Gli-1 does not undergo proteasomal degradation, and in the absence of ligand, Gli-2 is preferentially completely degraded in the proteasome while Gli-3 is partially degraded, and hence Gli-1 and Gli-2 act mostly as transcription promoters and Gli-3 can act as a transcription repressor.
Figure 2
Figure 2. Summary of the hedgehog pathway in the different hepatic cell types
See this image and copyright information in PMC

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