Article ; Online: Specific targeting of the NRF2/β-TrCP axis promotes beneficial effects in NASH.
2024 Volume 69, Page(s) 103027
Abstract: Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that compromises liver function, for which there is not a specifically approved medicine. Recent research has identified transcription factor NRF2 as a potential therapeutic target. ... ...
| Abstract | Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that compromises liver function, for which there is not a specifically approved medicine. Recent research has identified transcription factor NRF2 as a potential therapeutic target. However, current NRF2 activators, designed to inhibit its repressor KEAP1, exhibit unwanted side effects. Alternatively, we previously introduced PHAR, a protein-protein interaction inhibitor of NRF2/β-TrCP, which induces a mild NRF2 activation and selectively activates NRF2 in the liver, close to normal physiological levels. Herein, we assessed the effect of PHAR in protection against NASH and its progression to fibrosis. We conducted experiments to demonstrate that PHAR effectively activated NRF2 in hepatocytes, Kupffer cells, and stellate cells. Then, we used the STAM mouse model of NASH, based on partial damage of endocrine pancreas and insulin secretion impairment, followed by a high fat diet. Non-invasive analysis using MRI revealed that PHAR protects against liver fat accumulation. Moreover, PHAR attenuated key markers of NASH progression, including liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. Notably, transcriptomic data indicate that PHAR led to upregulation of 3 anti-fibrotic genes (Plg, Serpina1a, and Bmp7) and downregulation of 6 pro-fibrotic (including Acta2 and Col3a1), 11 extracellular matrix remodeling, and 8 inflammatory genes. Overall, our study suggests that the mild activation of NRF2 via the protein-protein interaction inhibitor PHAR holds promise as a strategy for addressing NASH and its progression to liver fibrosis. |
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| MeSH term(s) | Animals ; Mice ; beta-Transducin Repeat-Containing Proteins ; Fibrosis ; Kelch-Like ECH-Associated Protein 1/genetics ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/drug therapy |
| Chemical Substances | beta-Transducin Repeat-Containing Proteins ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Btrc protein, mouse ; Nfe2l2 protein, mouse |
| Language | English |
| Publishing date | 2024-01-03 |
| Publishing country | Netherlands |
| Document type | Journal Article |
| ZDB-ID | 2701011-9 |
| ISSN | 2213-2317 ; 2213-2317 |
| ISSN (online) | 2213-2317 |
| ISSN | 2213-2317 |
| DOI | 10.1016/j.redox.2024.103027 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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