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Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis.

Publication ,  Journal Article
Zhu, C; Kim, K; Wang, X; Bartolome, A; Salomao, M; Dongiovanni, P; Meroni, M; Graham, MJ; Yates, KP; Diehl, AM; Schwabe, RF; Tabas, I ...
Published in: Sci Transl Med
November 21, 2018

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.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

November 21, 2018

Volume

10

Issue

468

Location

United States

Related Subject Headings

  • SOX9 Transcription Factor
  • Receptors, Notch
  • Osteopontin
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Methionine
  • Male
  • Liver Cirrhosis
  • Humans
  • Hepatocytes
 

Citation

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Zhu, C., Kim, K., Wang, X., Bartolome, A., Salomao, M., Dongiovanni, P., … Pajvani, U. B. (2018). Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med, 10(468). https://doi.org/10.1126/scitranslmed.aat0344
Zhu, Changyu, KyeongJin Kim, Xiaobo Wang, Alberto Bartolome, Marcela Salomao, Paola Dongiovanni, Marica Meroni, et al. “Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis.Sci Transl Med 10, no. 468 (November 21, 2018). https://doi.org/10.1126/scitranslmed.aat0344.
Zhu C, Kim K, Wang X, Bartolome A, Salomao M, Dongiovanni P, et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2018 Nov 21;10(468).
Zhu, Changyu, et al. “Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis.Sci Transl Med, vol. 10, no. 468, Nov. 2018. Pubmed, doi:10.1126/scitranslmed.aat0344.
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. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2018 Nov 21;10(468).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

November 21, 2018

Volume

10

Issue

468

Location

United States

Related Subject Headings

  • SOX9 Transcription Factor
  • Receptors, Notch
  • Osteopontin
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Methionine
  • Male
  • Liver Cirrhosis
  • Humans
  • Hepatocytes