Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor kB (NF-kB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)–modified siRNA, both of which reduced NASH diet–induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.

Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis / J. Yu, C. Zhu, X. Wang, K. Kim, A. Bartolome, P. Dongiovanni, K.P. Yates, L. Valenti, M. Carrer, T. Sadowski, L. Qiang, I. Tabas, J.E. Lavine, U.B. Pajvani. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 13:599(2021 Jun 23), pp. eabe1692.1-eabe1692.11. [10.1126/scitranslmed.abe1692]

Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

P. Dongiovanni;L. Valenti;
2021-06-23

Abstract

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor kB (NF-kB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)–modified siRNA, both of which reduced NASH diet–induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.
Animals; Disease Models, Animal; Hepatocytes; Humans; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Mice, Knockout; Jagged-1 Protein; Non-alcoholic Fatty Liver Disease; Receptors, Notch; Signal Transduction; Toll-Like Receptor 4
Settore MED/09 - Medicina Interna
JTI_IMI17LVALE_01 - Liver Investigation: Testing Marker Utility in Steatohepatitis - VALENTI, LUCA VITTORIO CARLO - JTI_IMI - Joint Technology Iniziative_Innovative Medicines Initiative (IMI) - 2017
https://stm.sciencemag.org/content/13/599/eabe1692
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/861442
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