Research ArticleLiver disease

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

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Science Translational Medicine  21 Nov 2018:
Vol. 10, Issue 468, eaat0344
DOI: 10.1126/scitranslmed.aat0344

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Taking liver fibrosis down a Notch

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fat accumulation, inflammation, and liver cell damage. Here, Zhu et al. focused on Notch signaling in NASH and associated liver fibrosis. Expression of Notch target genes was increased in liver biopsies from patients with more severe NASH, and a mouse model of diet-induced NASH showed increased hepatocyte Notch expression. Notch signaling activated hepatic stellate cells, leading to liver fibrosis. Inhibiting Notch signaling using a liver-targeted antisense oligonucleotide reduced liver fibrosis in a diet-induced NASH mouse model. This study suggests that targeting hepatocyte Notch signaling could be therapeutic for NASH-associated liver fibrosis.

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.

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