Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis
Open accessAbstract
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.
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A nanoparticle-based γ-secretase inhibitor that blocks NOTCH activity reduced MASH fibrosis in mice.
“A nanoparticle-based approach to target γ-secretase inhibitor and block NOTCH activity reduced MASH fibrosis in mice (156).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [156]
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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
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- Authors
- Richter, L. R., Wan, Q., Wen, D., Zhang, Y., Yu, J., Kang, J. K., Zhu, C., McKinnon, E. L., Gu, Z., Qiang, L., & Pajvani, U. B.
- Affiliations
- Columbia University (US)
- University of North Carolina at Chapel Hill (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of British Columbia (CA)
- Corresponding author
- Gu, Zhen
- Qiang, Li
- Pajvani, Utpal B.
- ORCID
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-05-22
- Volume
- 14
- Issue
- 6
- Pages
- 6878-6886
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- PMC
- PMC7444843
- OpenAlex
- W3028438350
- Cited by
- 59
- References
- 47
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 15 · 2021: 11 · 2020: 2
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103818, R01DK112943, R01DK119767)
- University of California, Los Angeles
- Endocrine Fellows Foundation
- Russell Berrie Foundation
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Notch signaling, gamma-secretase inhibitors, obesity, type 2 diabetes, nonalcoholic steatohepatitis, liver fibrosis, impaired glucose tolerance, hepatic glucose production, nanoparticle drug delivery, liver-targeted drug delivery, goblet cell metaplasia, drug repurposing, diet-induced obesity
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Liver, Liver Cirrhosis, Obesity, Glucose Intolerance, Mice
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