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

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 (<i>JAG1</i>) 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 <i>Jag1</i> was mediated by hepatocyte Toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific <i>Jag1</i> 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 <i>Jag1</i> knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a <i>Jag1</i>-directed antisense oligonucleotide (ASO) and a hepatocyte-specific <i>N</i>-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.