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Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver diseases. Fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast like phenotype that is contractile, proliferative and profibrogenic. Hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. HIF activation during HSC activation can by either due to localised decreases in oxygen levels, or through oxygen-independent mechanisms that are not completely understood. Here we describe a role for the deubiquitinase UCHL1 in regulating HIF levels and activity during HSC activation and liver fibrosis. 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. UCHL1 specifically cleaves the degradative ubiquitin chains from HIF1α leading to increased HIF1α levels, even in sufficiently oxygenated cells. 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. These results demonstrate how small molecule inhibitors of DUBs can modulate the activity of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity via modulation of the ubiquitin-proteasomal degradation pathway may represent a therapeutic opportunity with other HIF-related pathologies.Abstract Figure |
