Research ArticleLIVER FIBROSIS

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

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Science Translational Medicine  23 Jun 2021:
Vol. 13, Issue 599, eabe1692
DOI: 10.1126/scitranslmed.abe1692

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A ligand for Notch in NASH

Notch activation is known to occur during the development of nonalcoholic steatohepatitis (NASH)–associated liver fibrosis. Using mouse NASH models and human liver samples, Yu et al. now show that a TLR4–NF-κB–mediated increase in the Notch ligand Jagged1 is responsible for this aberrant, fibrosis-inducing Notch reactivation. Antisense oligonucleotide and siRNA approaches against JAG1 also reduced liver fibrosis in a mouse model of NASH, suggesting the potential of Jagged1 as a therapeutic target.

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 κB (NF-κB) 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.

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