aat0344_Combined version.pdf

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.