Nonalcoholic steatohepatitis (NASH) is a serious health condition associated with the accumulation of lipids in the liver which leads to chronic inflammation. This inflammation can predispose affected individuals to serious downstream health problems including cirrhosis and hepatocellular carcinoma. NASH occurs in a wide variety of patients but has a number of known risk factors, including: obesity; glucose intolerance; and metabolic syndrome. While the majority of patients are between 40 and 60 years old, the increasing prevalence of obesity has made NASH a concern for all age groups. Despite these known risk factors, no pharmacologic interventions exist, and current therapies focus primarily on changes to lifestyle to try and mitigate steatosis in the liver and the development of fibrosis and inflammation that stems from it. This fibrotic phenotype is of particular concern as it appears to activate potent immune responses that underlie the inflammatory phenotype which portends eventual cirrhosis. The fibrotic and inflammatory responses are complex in NASH but are at least partially reflective of NF-?B mediated signaling events which regulate a number of pro-inflammatory cytokines secreted by steatotic hepatocytes. The ubiquitin proteasome system plays an important role in regulating NF-?B signaling, in particular through the deubiquitnase CYLD. As a down-regulator of both canonical and non-canonicals NF-?B signaling, CYLD has been shown to be an important protective factor against NASH. CYLD is regulated by the E3 Ligase TRIM47, which mediates its degradation. As such, inhibition of TRIM47 would stabilize CYLD and likely mitigate the detrimental effects of NF-?B signaling in NASH. Phase I of this grant would focus on the development of HTS assays to identify TRIM47 inhibitors which can stabilize CYLD and mitigate the development of steatosis in response to lipotoxicity. Phase II will focus on hit to lead development and the evaluation of lead compounds in animal models of NASH. The ultimate commercial goal of this project is the identification of small molecule TRIM47 inhibitors.
In non-alcoholic steatohepatitis (NASH), lipids accumulate in the liver and produce chronic inflammation, which can result in serious and life-threatening liver disorders; there is currently no cure. Recently, a ubiquitin protease called CYLD has been shown to protect against development of NASH; it can be removed from cells, however, by a ubiquitin ligase called TRIM47, which causes its degradation. This application proposes to develop selective inhibitors of TRIM47 that will protect CYLD in cells and thereby provide benefit for patients with NASH.
