Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis.

Published

Journal Article

Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet-fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, we found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet-fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

Full Text

Duke Authors

Cited Authors

  • Zhu, C; Kim, K; Wang, X; Bartolome, A; Salomao, M; Dongiovanni, P; Meroni, M; Graham, MJ; Yates, KP; Diehl, AM; Schwabe, RF; Tabas, I; Valenti, L; Lavine, JE; Pajvani, UB

Published Date

  • November 21, 2018

Published In

Volume / Issue

  • 10 / 468

PubMed ID

  • 30463916

Pubmed Central ID

  • 30463916

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aat0344

Language

  • eng

Conference Location

  • United States