nn0c01007_si_001.pdf (675.05 kB)
Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis
Version 2 2020-05-28, 17:38
Version 1 2020-05-22, 15:07
journal contribution
posted on 2020-05-28, 17:38 authored by Lauren R. Richter, Qianfen Wan, Di Wen, Yuqi Zhang, Junjie Yu, Jin ku Kang, Changyu Zhu, Elizabeth L. McKinnon, Zhen Gu, Li Qiang, Utpal B. PajvaniAs
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.
History
Usage metrics
Categories
Keywords
obesity-induced T 2DMhepatic fibrosisnanoparticle-mediated delivery systemNotch antagonismtarget γ- secretase inhibitorobesity-induced type 2 diabetes mellitusgoblet cell metaplasiaNotch Inhibitor Attenuates Obesity-Induced Glucose IntoleranceGSI NPsnonalcoholic steatohepatitishepatic glucose productiondelivery methodNASH-provoking dietextrahepatic side effectsT 2DMGSI NP applicationliver fibrosispharmacologic therapiesγ- secretase inhibitorsTargeted DeliveryLiver Fibrosis
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC