Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis

Yosuke Osawa; Hironari Kawai; Keigo Nakashima; Yuichi Nakaseko; Daisuke Suto; Keisuke Yanagida; Tomomi Hashidate-Yoshida; Taizo Mori; Sachiyo Yoshio; Takaaki Ohtake; Hideo Shindou; Tatsuya Kanto

doi:10.1371/journal.pone.0303296

Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis

PLoS One. 2024 May 16;19(5):e0303296. doi: 10.1371/journal.pone.0303296. eCollection 2024.

Authors

Yosuke Osawa^{1

2}, Hironari Kawai^{2

3}, Keigo Nakashima^{3

4}, Yuichi Nakaseko^{3

4}, Daisuke Suto¹, Keisuke Yanagida⁵, Tomomi Hashidate-Yoshida⁵, Taizo Mori², Sachiyo Yoshio², Takaaki Ohtake¹, Hideo Shindou^{5

6}, Tatsuya Kanto²

Affiliations

¹ Departments of Gastroenterology, International University of Health and Welfare Hospital, Tochigi, Japan.
² Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.
³ Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
⁴ Departments of Surgery, International University of Health and Welfare Hospital, Tochigi, Japan.
⁵ Departments of Lipid Life Science, National Center for Global Health and Medicine, Tokyo, Japan.
⁶ Departments of Medical Lipid Science, Graduated Scholl of Medicine, The University of Tokyo, Tokyo, Japan.

Abstract

Aim: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH.

Methods: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.

Results: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.

Conclusion: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.

Copyright: © 2024 Osawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Animals
Choline Deficiency / complications
Choline Deficiency / metabolism
Endothelial Cells / metabolism
Endothelial Cells / pathology
Fatty Liver* / metabolism
Fatty Liver* / pathology
Hepatic Stellate Cells* / metabolism
Hepatic Stellate Cells* / pathology
Humans
Liver / metabolism
Liver / pathology
Liver Cirrhosis* / etiology
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Lysophospholipids* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphotransferases (Alcohol Group Acceptor)* / genetics
Phosphotransferases (Alcohol Group Acceptor)* / metabolism
Pyrazoles
Pyridines
Receptors, Lysosphingolipid / genetics
Receptors, Lysosphingolipid / metabolism
Sphingosine* / analogs & derivatives
Sphingosine* / metabolism
Sphingosine-1-Phosphate Receptors* / metabolism

Substances

sphingosine 1-phosphate
Sphk1 protein, mouse
sphingosine-1-phosphate receptor-2, mouse
sphingosine kinase
JTE 013

Grants and funding

This study was supported by grants from the JSPS KAKENHI to Y.O. (21K08014) and H.K. (23K15507), IUHW Research Grant to Y.O., the Japan Agency for Medical Research and Development (AMED, 23fk0210091h0003) to T.K. and H.S., the National Center for Global Health and Medicine, Intramural Research Fund (22T001) to H.S., and a Grant-in-Aid for Research from the National Center for Global Health and Medicine (20A1001 to T.K., and 22A1012 to K.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.