Investigating the therapeutic potential of REV-ERB⍺ activation in chronic inflammatory diseases

Abstract

Metabolic-associated steatohepatitis (MASH) is a metabolic disease of the liver, that manifests itself as steatohepatitis, inflammation, and fibrosis. It has the potential to progress to cirrhosis and hepatocellular carcinoma if uncontrolled. Currently, there is no effective treatment strategy except lifestyle changes. It is imperative to develop therapeutics against MASH and alleviate the leading cause of liver transplants across the world. We and others have shown that nuclear receptor REV-ERB plays a significant protective role in liver biology by acting as a transcriptional repressor of important genes involved in metabolism, inflammation, and fibrosis. While we have shown that in-vivo administration of REV-ERB agonist SR9009 is able to alleviate symptoms of MASH such as inflammation and fibrosis, we are yet to find out its mechanism of action. Additionally, SR9009 has its limitations in terms of solubility and efficacy. In this dissertation, we utilize a relatively novel REV-ERB agonist STL1267 and explore its efficacy in the treatment of MASH. We also explore its mechanism of action using in-vitro and in-vivo mouse models. We found that STL1267 is more effective in treating MASH, with increased reduction in triglycerides, inflammation, and fibrosis. We were able to show that REV-ERB agonism acts via metabolically reprogramming energy metabolism in cells associated with MASH. It reduces mitochondrial metabolism, and alleviates metabolic stress, reducing the further downstream effects such as oxidative stress, mitochondrial dysfunction, inflammation, and fibrosis in cells such as hepatocytes, stellate cells, and macrophages.