Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Abstract

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.

Cell-in-Cell Structures in the Liver: A Tale of Four E’s

“…The molecular mechanisms controlling hepatocellular injury have begun to emerge in recent studies that revealed a role for the transcription regulator TAZ in preventing hepatocyte death, inflammation and fibrosis (87,88). Further, hepatocyte Notch activation was linked directly to NASH-related fibrosis (89). The role of efferocytosis in the clearance of apoptotic cells and the prevention of necrotic cell injury and fibrosis in NASH has been reviewed recently (90).…”

Expression of Notch family is altered in non‑alcoholic fatty liver disease

“…in patients with naSH, notch activity in hepatocytes was associated with severity and responsiveness to treatment (30). In Notch loss-of-function mouse models, hepatocyte-specific liver inflammation and fibrosis are reduced, suggesting maladaptive hepatocytic notch response in naSH-associated liver fibrosis (30). In the present study, the dynamic effect of notch genes during naFld development in vivo was evaluated.…”

Does Mechanocrine Signaling by Liver Sinusoidal Endothelial Cells Offer New Opportunities for the Development of Anti-fibrotics?

“…As mentioned previously (section NOTCH), Notch has diverse functions during liver development, homeostasis and disease (57). In hepatocytes (58) or LSECs (43) Notch signaling can induce HSC activation and promotes fibrosis. It has been demonstrated that inhibition of Notch signaling using a GSI in vivo ameliorated fibrosis in a CCl4 pre-clinical model (59).…”