Browse by author
Lookup NU author(s): Amy Collins, Rebecca Scott, Dr Caroline WilsonORCiD, Dr Giuseppe Abbate, Steven White, Jeremy French, John Moir, Colin Wilson, Professor Sanjay PandanaboyanaORCiD, John Hammond, Professor Fiona OakleyORCiD, Professor Jelena Mann, Professor Derek Mann
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s)Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver disease. At the cellular level, liver fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast-like phenotype that is contractile, proliferative and profibrogenic. HSC transdifferentiation induces genome-wide changes in gene expression that enable the cell to adopt its profibrogenic functions. We have previously identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation; however, the cellular targets of its deubiquitinating activity are poorly defined. Here, we describe a role for UCHL1 in regulating the levels and activity of hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, during HSC activation and liver fibrosis. HIF1 is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. Increased HIF1α expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1α levels. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. As we also show that UCHL1 inhibition blunts fibrogenesis in a pre-clinical 3D human liver slice model of fibrosis, these results demonstrate how small molecule inhibitors of DUBs can exert therapeutic effects through modulation of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity using UCHL1 inhibitors may represent a therapeutic opportunity with other HIF-related pathologies.
Author(s): Collins A, Scott R, Wilson CL, Abbate G, Ecclestone GB, Albanese AG, Biddles D, White S, French J, Moir J, Alrawashdeh W, Wilson C, Pandanaboyana S, Hammond JS, Thakkar R, Oakley F, Mann J, Mann DA, Kenneth NS
Publication type: Article
Publication status: Published
Journal: Bioscience Reports
Year: 2024
Volume: 44
Issue: 6
Print publication date: 01/06/2024
Online publication date: 29/05/2024
Acceptance date: 28/05/2024
Date deposited: 01/07/2024
ISSN (print): 0144-8463
ISSN (electronic): 1573-4935
Publisher: Portland Press Ltd
URL: https://doi.org/10.1042/BSR20232147
DOI: 10.1042/BSR20232147
Data Access Statement: All data are available in the manuscript. Raw files for immunoblot analysis are provided in the supplementary information.
PubMed id: 38808772
Altmetrics provided by Altmetric
