2. Academic Validation
  3. Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome

Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome

  • Cell Mol Gastroenterol Hepatol. 2022;13(3):925-947. doi: 10.1016/j.jcmgh.2021.12.002.
Chung Hwan Hong 1,  Myoung Seok Ko 2,  Jae Hyun Kim 3,  Hyunkyung Cho 4,  Chi-Ho Lee 5,  Ji Eun Yoon 1,  Ji-Young Yun 2,  In-Jeoung Baek 6,  Jung Eun Jang 7,  Seung Eun Lee 7,  Yun Kyung Cho 7,  Ji Yeon Baek 7,  Soo Jin Oh 8,  Bong Yong Lee 9,  Joon Seo Lim 10,  Jongkook Lee 11,  Sean M Hartig 12,  Laura Conde de la Rosa 13,  Carmen Garcia-Ruiz 14,  Ki-Up Lee 15,  Jose C Fernández-Checa 16,  Ji Woong Choi 17,  Sanghee Kim 18,  Eun Hee Koh 19
Affiliations

Affiliations

  • 1 Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 2 Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 3 College of Pharmacy, Seoul National University, Seoul, Korea; College of Pharmacy, Kangwon National University, Chuncheon, Korea.
  • 4 College of Pharmacy, Seoul National University, Seoul, Korea.
  • 5 College of Pharmacy, Gachon University, Incheon, Korea.
  • 6 Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 7 Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 8 New Drug Development Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 9 Nextgen Bioscience, Seongnam, Korea.
  • 10 Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 11 College of Pharmacy, Kangwon National University, Chuncheon, Korea.
  • 12 Molecular and Cellular Biology, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas.
  • 13 Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona and Liver Unit-Hospital Clinic-Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona, Spain.
  • 14 Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona and Liver Unit-Hospital Clinic-Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona, Spain; Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, California.
  • 15 Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 16 Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona and Liver Unit-Hospital Clinic-Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona, Spain; Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: [email protected].
  • 17 College of Pharmacy, Gachon University, Incheon, Korea. Electronic address: [email protected].
  • 18 College of Pharmacy, Seoul National University, Seoul, Korea. Electronic address: [email protected].
  • 19 Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Electronic address: [email protected].
PMID: 34890841 DOI: 10.1016/j.jcmgh.2021.12.002
Abstract

Background & aims: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear.

Methods: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library.

Results: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1PR4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1PR4+/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1PR4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated CA++ release and deactivated the NOD-like Receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1PR4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [CA++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1PR4+/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome.

Conclusions: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.

Keywords

Ca(++); Functional Antagonist; Hepatic Macrophages; S1P.

Figures