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

Sci Transl Med. 2019 Jun 12;11(496):eaat9284. doi: 10.1126/scitranslmed.aat9284.

Authors

Yoon Mee Yang^{1

2}, Mazen Noureddin^{1

3}, Cheng Liu⁴, Koichiro Ohashi¹, So Yeon Kim¹, Divya Ramnath⁵, Elizabeth E Powell^{6

7}, Matthew J Sweet⁵, Yoon Seok Roh^{1

8}, I-Fang Hsin¹, Nan Deng⁹, Zhenqiu Liu⁹, Jiurong Liang^{1

10

11}, Edward Mena¹², Daniel Shouhed¹³, Robert F Schwabe¹⁴, Dianhua Jiang^{1

10

11}, Shelly C Lu¹, Paul W Noble^{1

10}, Ekihiro Seki^{15

11}

Affiliations

¹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea.
³ Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴ Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
⁵ Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, University of Queensland, Brisbane, Queensland 4072, Australia.
⁶ Centre for Liver Disease Research, University of Queensland, Brisbane, Queensland, Australia.
⁷ Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
⁸ Department of Pharmacy, Chungbuk National University College of Pharmacy, Cheongju, Chungbuk 28160, South Korea.
⁹ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹¹ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹² California Liver Research Institute, Pasadena, CA 91105, USA.
¹³ Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁴ Department of Medicine, Columbia University, New York, NY 10032, USA.
¹⁵ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Enzyme-Linked Immunosorbent Assay
HEK293 Cells
Hepatic Stellate Cells / drug effects
Hepatic Stellate Cells / metabolism*
Humans
Hyaluronan Receptors / metabolism
Hyaluronan Synthases / metabolism*
Hyaluronic Acid / metabolism*
Hymecromone / pharmacology
Liver Cirrhosis / metabolism*
RNA-Seq
Toll-Like Receptor 4 / metabolism

Substances

Hyaluronan Receptors
Toll-Like Receptor 4
Hymecromone
Hyaluronic Acid
Hyaluronan Synthases

Abstract

Publication types

MeSH terms

Substances

Grants and funding