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ResearchIn-Press PreviewHepatology Free access | 10.1172/JCI143690

Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis

Kunimaro Furuta,1 Qianqian Guo,1 Kevin D. Pavelko,2 Jeong-Heon Lee,3 Keith D. Robertson,4 Yasuhiko Nakao,1 Jan Melek,5 Vijay H. Shah,1 Petra Hirsova,1 and Samar H. Ibrahim6

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Furuta, K. in: JCI | PubMed | Google Scholar

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Guo, Q. in: JCI | PubMed | Google Scholar |

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Pavelko, K. in: JCI | PubMed | Google Scholar |

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Lee, J. in: JCI | PubMed | Google Scholar |

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Robertson, K. in: JCI | PubMed | Google Scholar |

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Nakao, Y. in: JCI | PubMed | Google Scholar

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Melek, J. in: JCI | PubMed | Google Scholar |

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Shah, V. in: JCI | PubMed | Google Scholar

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

Find articles by Hirsova, P. in: JCI | PubMed | Google Scholar |

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States of America

2Department of Immunology, Mayo Clinic, Rochester, United States of America

3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States of America

4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

5Department of Pediatrics, Charles University in Prague, Hradec Králové, Czech Republic

6Division of Pediatric Gastroenterology, Mayo Cinic, Rochester, United States of America

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Published January 21, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI143690.
Copyright © 2021, American Society for Clinical Investigation
Published January 21, 2021 - Version history
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Abstract

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSEC) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that vascular cell adhesion molecule 1 (VCAM-1) mediates monocyte adhesion to LSEC. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC-VCAM-1 in murine NASH. Moreover, LSEC-VCAM-1 expression was significantly increased in human NASH. LSEC-VCAM-1 expression was upregulated by palmitate treatment in vitro, and reduced with inhibition of the mitogen-activated protein 3 kinase, mixed lineage kinase 3 (MLK3). Likewise, LSEC-VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing antibody or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC-VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH, and might serve as a potential therapeutic strategy for human NASH.

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