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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in Western countries[1]
As part of this effort, we investigated the role of a small-molecule inhibitor of the Bromodomain and Extra-Terminal domain (BET) family of proteins, GSK1210151A (I-BET151)[20,21], in a pre-clinical mouse Non-alcoholic steatohepatitis (NASH) STAM model[22] to assess its efficacy against NASH and hepatic fibrosis
We found that therapeutic intervention with I-BET151 resulted in significant reduction in non-alcoholic fatty liver disease activity score (NAS) and improvement in liver fibrosis scores in the STAM mice
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in Western countries[1]. NAFLD encompasses a spectrum of fatty liver diseases observed in individuals that do not consume excessive alcohol, ranging from simple steatosis to steatosis accompanied by hepatocyte ballooning and inflammation (referred to as nonalcoholic steatohepatitis, NASH) and fibrosis[2]. Given the existing evidence relating BET and liver fibrosis, plus an association via connectivity map (CMAP)[19] to NASH which we report here, we decided to further validate this mechanism. As part of this effort, we investigated the role of a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151)[20,21], in a pre-clinical mouse NASH STAM model[22] to assess its efficacy against NASH and hepatic fibrosis. The results from our study suggest that BET inhibition may represent a novel therapy for the treatment of NASH and other fibrotic liver diseases
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