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

Yoon Mee Yang, Mazen Noureddin, Cheng Liu, Koichiro Ohashi, So Yeon Kim, Divya Ramnath, Elizabeth E. Powell, Matthew J. Sweet, Yoon Seok Roh, I. Fang Hsin, Nan Deng, Zhenqiu Liu, Jiurong Liang, Edward Mena, Daniel Shouhed, Robert F. Schwabe, Dianhua Jiang, Shelly C. Lu, Paul W. Noble, Ekihiro Seki

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbereaat9284
JournalScience Translational Medicine
Volume11
Issue number496
DOIs
StatePublished - Jun 12 2019

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Hyaluronic Acid
Liver Cirrhosis
Hepatic Stellate Cells
Hymecromone
Toll-Like Receptor 4
Wilms Tumor
Transforming Growth Factors
hyaluronan synthase
Glycosaminoglycans
Extracellular Matrix
Fibrosis
Biomarkers
Liver

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Yang, Y. M., Noureddin, M., Liu, C., Ohashi, K., Kim, S. Y., Ramnath, D., ... Seki, E. (2019). Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Science Translational Medicine, 11(496), [eaat9284]. https://doi.org/10.1126/scitranslmed.aat9284
Yang, Yoon Mee ; Noureddin, Mazen ; Liu, Cheng ; Ohashi, Koichiro ; Kim, So Yeon ; Ramnath, Divya ; Powell, Elizabeth E. ; Sweet, Matthew J. ; Roh, Yoon Seok ; Hsin, I. Fang ; Deng, Nan ; Liu, Zhenqiu ; Liang, Jiurong ; Mena, Edward ; Shouhed, Daniel ; Schwabe, Robert F. ; Jiang, Dianhua ; Lu, Shelly C. ; Noble, Paul W. ; Seki, Ekihiro. / Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. In: Science Translational Medicine. 2019 ; Vol. 11, No. 496.
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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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Yang, YM, Noureddin, M, Liu, C, Ohashi, K, Kim, SY, Ramnath, D, Powell, EE, Sweet, MJ, Roh, YS, Hsin, IF, Deng, N, Liu, Z, Liang, J, Mena, E, Shouhed, D, Schwabe, RF, Jiang, D, Lu, SC, Noble, PW & Seki, E 2019, 'Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis', Science Translational Medicine, vol. 11, no. 496, eaat9284. https://doi.org/10.1126/scitranslmed.aat9284

Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. / Yang, Yoon Mee; Noureddin, Mazen; Liu, Cheng; Ohashi, Koichiro; Kim, So Yeon; Ramnath, Divya; Powell, Elizabeth E.; Sweet, Matthew J.; Roh, Yoon Seok; Hsin, I. Fang; Deng, Nan; Liu, Zhenqiu; Liang, Jiurong; Mena, Edward; Shouhed, Daniel; Schwabe, Robert F.; Jiang, Dianhua; Lu, Shelly C.; Noble, Paul W.; Seki, Ekihiro.

In: Science Translational Medicine, Vol. 11, No. 496, eaat9284, 12.06.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis

AU - Yang, Yoon Mee

AU - Noureddin, Mazen

AU - Liu, Cheng

AU - Ohashi, Koichiro

AU - Kim, So Yeon

AU - Ramnath, Divya

AU - Powell, Elizabeth E.

AU - Sweet, Matthew J.

AU - Roh, Yoon Seok

AU - Hsin, I. Fang

AU - Deng, Nan

AU - Liu, Zhenqiu

AU - Liang, Jiurong

AU - Mena, Edward

AU - Shouhed, Daniel

AU - Schwabe, Robert F.

AU - Jiang, Dianhua

AU - Lu, Shelly C.

AU - Noble, Paul W.

AU - Seki, Ekihiro

PY - 2019/6/12

Y1 - 2019/6/12

N2 - 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.

AB - 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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