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

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein,...

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Published in:The Journal of clinical investigation Vol. 131; no. 6; pp. 1 - 16
Main Authors: Furuta, Kunimaro, Guo, Qianqian, Pavelko, Kevin D., Lee, Jeong-Heon, Robertson, Keith D., Nakao, Yasuhiko, Melek, Jan, Shah, Vijay H., Hirsova, Petra, Ibrahim, Samar H.
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 15.03.2021
Subjects:
Animals
Antibodies, Neutralizing - administration & dosage
Atherosclerosis
Biomedical research
Cell adhesion & migration
Cell adhesion molecules
Chromatin
Cytometry
Development and progression
Diet
Disease Models, Animal
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Endothelium
Fatty acids
Fatty liver
Gene expression
Gene Expression Profiling
Genes
Genomes
Health aspects
Hepatocytes
Humans
Inflammation
Kinases
Liver - drug effects
Liver - metabolism
Liver - pathology
Liver diseases
MAP kinase
MAP kinase kinase
MAP Kinase Signaling System - drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes
Non-alcoholic Fatty Liver Disease - etiology
Non-alcoholic Fatty Liver Disease - genetics
Non-alcoholic Fatty Liver Disease - metabolism
Palmitates - toxicity
Palmitic acid
Pathogenesis
Physiological aspects
Protein expression
Proteins
RNA, Messenger - genetics
Transcription
Transcriptomes
Up-Regulation - drug effects
Vascular cell adhesion molecule 1
Vascular Cell Adhesion Molecule-1 - antagonists & inhibitors
Vascular Cell Adhesion Molecule-1 - genetics
Vascular Cell Adhesion Molecule-1 - metabolism
United States
Cell migration/adhesion
Hepatology
Endothelial cells
ISSN:0021-9738, 1558-8238, 1558-8238
Online Access:Get full text
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Summary:Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. 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 (MAP3K) mixed lineage kinase 3 (MLK3). Likewise, LSEC VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing Ab 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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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI143690