aat0344_Combined version.pdf

Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH)<br>but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms.<br>Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with<br>NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific<br>Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality<br>to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both<br>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<br>the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch<br>inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary,<br>these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte<br>Notch response in NASH-associated liver fibrosis.