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

Research ArticleLIVER FIBROSIS

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

View ORCID ProfileYoon Mee Yang ¹,²,
View ORCID ProfileMazen Noureddin ¹,³,*,
Cheng Liu ⁴,*,
Koichiro Ohashi¹,
View ORCID ProfileSo Yeon Kim¹,
View ORCID ProfileDivya Ramnath⁵,
Elizabeth E. Powell⁶,⁷,
View ORCID ProfileMatthew J. Sweet ⁵,
Yoon Seok Roh ¹,⁸,
I-Fang Hsin¹,
Nan Deng⁹,
Zhenqiu Liu⁹,
View ORCID ProfileJiurong Liang¹,¹⁰,¹¹,
View ORCID ProfileEdward Mena¹²,
Daniel Shouhed¹³,
View ORCID ProfileRobert F. Schwabe¹⁴,
View ORCID ProfileDianhua Jiang ¹,¹⁰,¹¹,
Shelly C. Lu ¹,
Paul W. Noble ¹,¹⁰ and
View ORCID ProfileEkihiro Seki ¹,¹¹,†

¹Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
²College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea.
³Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
⁵Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, University of Queensland, Brisbane, Queensland 4072, Australia.
⁶Centre for Liver Disease Research, University of Queensland, Brisbane, Queensland, Australia.
⁷Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
⁸Department of Pharmacy, Chungbuk National University College of Pharmacy, Cheongju, Chungbuk 28160, South Korea.
⁹Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹¹Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹²California Liver Research Institute, Pasadena, CA 91105, USA.
¹³Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁴Department of Medicine, Columbia University, New York, NY 10032, USA.

↵†Corresponding author. Email: ekihiro.seki{at}cshs.org

↵* These authors contributed equally to this work.

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

Yoon Mee Yang

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

2College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea.

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Mazen Noureddin

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

3Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Cheng Liu

4Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.

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Koichiro Ohashi

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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So Yeon Kim

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Divya Ramnath

5Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, University of Queensland, Brisbane, Queensland 4072, Australia.

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Elizabeth E. Powell

6Centre for Liver Disease Research, University of Queensland, Brisbane, Queensland, Australia.

7Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.

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Matthew J. Sweet

5Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, University of Queensland, Brisbane, Queensland 4072, Australia.

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Yoon Seok Roh

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

8Department of Pharmacy, Chungbuk National University College of Pharmacy, Cheongju, Chungbuk 28160, South Korea.

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I-Fang Hsin

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Nan Deng

9Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Zhenqiu Liu

9Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Jiurong Liang

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

10Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

11Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Edward Mena

12California Liver Research Institute, Pasadena, CA 91105, USA.

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Daniel Shouhed

13Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Robert F. Schwabe

14Department of Medicine, Columbia University, New York, NY 10032, USA.

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Dianhua Jiang

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

10Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

11Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Shelly C. Lu

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Paul W. Noble

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

10Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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Ekihiro Seki

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

11Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

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For correspondence: ekihiro.seki@cshs.org

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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.

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

HAlting liver fibrosis

Science Translational Medicine

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