Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis.

Abstract

As the prevalence of obesity-induced type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH) continue to increase, the need for pharmacologic therapies becomes urgent. However, endeavors to identify and develop novel therapeutic strategies for these chronic conditions are balanced by the need for safety, impeding clinical translation. One shared pathology of these two diseases is a maladaptive reactivation of the Notch signaling pathway in liver. Notch antagonism with γ-secretase inhibitors effectively suppresses hepatic glucose production and reduces liver fibrosis in NASH, but its extrahepatic side effects, particularly goblet cell metaplasia, limit therapeutic utility. To overcome this barrier, we developed a nanoparticle-mediated delivery system to target γ-secretase inhibitor to liver (GSI NPs). GSI NP application reduced hepatic glucose production in diet-induced obese mice and reduced hepatic fibrosis and inflammation in mice fed a NASH-provoking diet, without apparent gastrointestinal toxicity. By changing the delivery method, these results provide proof-of-concept for the repurposing of a previously intolerable medication to address unmet needs in the clinical landscape for obesity-induced T2DM and NASH.