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BET Inhibition Improves NASH and Liver Fibrosis
- Source :
- Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
- Subjects :
- Liver Cirrhosis
0301 basic medicine
Cirrhosis
lcsh:Medicine
Chronic liver disease
Heterocyclic Compounds, 4 or More Rings
Severity of Illness Index
digestive system
Article
Interferon-gamma
Mice
03 medical and health sciences
Non-alcoholic Fatty Liver Disease
Fibrosis
medicine
Animals
Humans
Gene Regulatory Networks
lcsh:Science
Multidisciplinary
Sequence Analysis, RNA
business.industry
Gene Expression Profiling
lcsh:R
Fatty liver
Computational Biology
nutritional and metabolic diseases
medicine.disease
digestive system diseases
Bromodomain
Gene expression profiling
Disease Models, Animal
Cholesterol
030104 developmental biology
Gene Expression Regulation
Hepatocellular carcinoma
Disease Progression
Cancer research
lcsh:Q
Steatohepatitis
business
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....724a5a83921aa094d82a284d7a0f7432