Research ArticleLIVER FIBROSIS

Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis

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Science Translational Medicine  12 Jun 2019:
Vol. 11, Issue 496, eaat9284
DOI: 10.1126/scitranslmed.aat9284

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HAlting liver fibrosis

Hepatic stellate cells (HSCs) play a key role in liver fibrosis, a process marked by the deposition of extracellular matrix including the glycosaminoglycan hyaluronan (HA). Here, Yang et al. investigated the mechanisms regulating HSCs and HA deposition using patient samples and mouse models. They found that HA synthase 2 was increased in HSCs in fibrotic patient and mouse liver tissues. HA and Notch1 signaling activated HSCs in an HA synthase 2–dependent process. Inhibiting HA synthesis reduced HSC activation and progression of liver fibrosis, identifying a therapeutic target.

Abstract

Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were reduced in mice lacking HAS2 in hepatic stellate cells (HSCs), whereas mice overexpressing HAS2 had exacerbated liver fibrosis. HAS2 was transcriptionally up-regulated by transforming growth factor–β through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4 (TLR4), and newly identified downstream effector Notch1. Inhibition of HA synthesis by 4-methylumbelliferone reduced HSC activation and liver fibrosis in mice. Our study provides evidence that HAS2 actively synthesizes HA in HSCs and that it promotes HSC activation and liver fibrosis through Notch1. Targeted HA inhibition may have potential to be an effective therapy for liver fibrosis.

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