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

• DOI: 10.1021/acsnano.0c01007
• Publication Date: 2020-05-22T15:05:59Z
• Authors: Lauren R. Richter; Qianfen Wan; Di Wen; Yuqi Zhang; Junjie Yu; Jin ku Kang; Changyu Zhu; Elizabeth L. McKi...; Zhen Gu; Li Qiang; Utpal B. Pajvani
• Keywords: Steatohepatitis; Nonalcoholic steatohepatitis

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