Effect of Hepatic Lipid Overload on Accelerated Hepatocyte Proliferation Promoted by HGF Expression via the SphK1/S1PR2 Pathway in MCD-diet Mouse Partial Hepatectomy

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  • Lkham-Erdene Baljinnyam
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki Thoracic surgery department, National Cancer Center, Ulaanbaatar, Mongolia
  • Choijookhuu Narantsog
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki Department of Pathology and Forensic Medicine, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
  • Kubota Toshiki
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki
  • Uto Tomofumi
    Division of Immunology, Department of Infectious diseases, Faculty of Medicine, University of Miyazaki
  • Mitoma Shuya
    Division of Immunology, Department of Infectious diseases, Faculty of Medicine, University of Miyazaki
  • Shirouzu Shinichiro
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki
  • Ishizuka Takumi
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
  • Kai Kengo
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
  • Higuchi Kazuhiro
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki Department of Surgery, Faculty of Medicine, University of Miyazaki
  • Mo Aung Kham
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
  • Batmunkh Jargal-Erdene
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
  • Sato Katsuaki
    Division of Immunology, Department of Infectious diseases, Faculty of Medicine, University of Miyazaki
  • Hishikawa Yoshitaka
    Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki

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<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming a major health problem worldwide. Liver regeneration is crucial for restoring liver function, and is regulated by extraordinary complex process, involving numerous factors under both physiologic and pathologic conditions. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid synthesized by sphingosine kinase 1 (SphK1), plays an important role in liver function through S1P receptors (S1PRs)-expressing cells. In this study, we investigated the effect of lipid overload on hepatocyte proliferation in a mouse hepatic steatosis model induced by feeding a methionine- and choline-deficient (MCD) diet. After 50% partial hepatectomy (PHx), liver tissues were sampled at various timepoints and then analyzed by immunohistochemistry, oil Red-O staining, quantitative-polymerase chain reaction (qPCR), and flow cytometry. In mice fed the MCD-diet, significantly exacerbated hepatic steatosis and accelerated liver regeneration were observed. After PHx, hepatocyte proliferation peaked at 48 and 36 hr in the liver of chow- and MCD-diet fed mice, respectively. By contrast, increased expression of S1PR2 was observed in hepatic neutrophils and macrophages of MCD-diet fed mice. Flow cytometry and qPCR experiments demonstrated that levels of HGF and FGF2 released by neutrophils and macrophages were significantly higher in MCD-diet fed mice. In conclusion, hepatic lipid overload recruits Kupffer cells and neutrophils that release HGF and FGF2 via SphK1/S1PR2 activation to accelerate hepatocyte proliferation.</p>

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