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

doi:10.1126/scitranslmed.aat9284

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

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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 language	English (US)
Article number	eaat9284
Journal	Science translational medicine
Volume	11
Issue number	496
DOIs	https://doi.org/10.1126/scitranslmed.aat9284
State	Published - Jun 12 2019

ASJC Scopus subject areas

Medicine(all)

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Yang, Y. M., Noureddin, M., Liu, C., Ohashi, K., Kim, S. Y., Ramnath, D., Powell, E. E., Sweet, M. J., Roh, Y. S., Hsin, I. F., Deng, N., Liu, Z., Liang, J., Mena, E., Shouhed, D., Schwabe, R. F., Jiang, D., Lu, S. C., Noble, P. W., & Seki, E. (2019). Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Science translational medicine, 11(496), Article eaat9284. https://doi.org/10.1126/scitranslmed.aat9284

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

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title = "Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis",

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.",

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

note = "Funding Information: National Natural Science Foundation of China (no. 81673788 to C.L.) Publisher Copyright: {\textcopyright} 2019 American Association for the Advancement of Science. All rights reserved.",

year = "2019",

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doi = "10.1126/scitranslmed.aat9284",

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AU - Liu, Cheng

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

Abstract

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