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Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis
Open accessAbstract
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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“During MASH, lipotoxic stimulation leads to increased expression of endothelial vascular cell adhesion molecule 1 (VCAM1) [315].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [315]
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“This activation involves the expression of adhesion proteins such as vascular cell adhesion molecule 1 (VCAM-1), which directly recruits pro-inflammatory and pro-fibrogenic immune cells into the liver, while also disrupting the quiescent state of HSCs (104) (105-109).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [108]
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Metadata
- Authors
- Furuta, K., Guo, Q., Pavelko, K. D., Lee, J.-H., Robertson, K. D., Nakao, Y., Melek, J., Shah, V. H., Hirsova, P., & Ibrahim, S. H.
- Affiliations
- Mayo Clinic (US)
- Charles University (CZ)
- Corresponding author
- Ibrahim, Samar H.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-03-15
- Volume
- 131
- Issue
- 6
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7954604
- OpenAlex
- W3125313120
- Cited by
- 136
- References
- 61
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 24 · 2023: 27 · 2022: 18 · 2021: 13
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Digestive And Kidney Diseases of the National Institutes of Health (DK 122948)
- American Association of Study of liver Disease (Pinnacle Research Award, Bridge Award)
- NIH Silvio O. Conte Digestive Diseases Research Core Centers P30 grant mechanism (DK084567)
- Japan Society for the Promotion of Science (202060532)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, VCAM-1, liver sinusoidal endothelial cells, monocyte adhesion, lipotoxicity, palmitate, MLK3, MAP3K signaling, endothelial adhesion molecules, diet-induced NASH, NASH therapy
- MeSH terms
- Animals, Disease Models, Animal, Humans, Liver, Mice, Inbred C57BL, Palmitates, RNA, Messenger, Up-Regulation, Mice, Knockout, Vascular Cell Adhesion Molecule-1, Gene Expression Profiling, MAP Kinase Signaling System, Endothelial Cells, Mice, Antibodies, Neutralizing, Non-alcoholic Fatty Liver Disease
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