Lipotoxicity Amplifies IL‐6 Trans‐Signaling in Sinusoidal Endothelial Cells to Promote Endotheliopathy and Liver Injury
- 1Department of General and Gastroenterological Surgery Osaka Medical and Pharmaceutical University Osaka Japan
- 2Department of Pathology Osaka Medical and Pharmaceutical University Osaka Japan
- 3Center for Research & Development, Division of Translational Research Osaka Medical and Pharmaceutical University Osaka Japan
Abstract
Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) affects approximately 25% of the global population and is a major health concern. Liver sinusoidal endothelial cells (LSECs) undergo morphological and functional alterations during MASLD progression, resulting in endotheliopathy characterized by pro‐inflammatory phenotypes. We hypothesize that lipotoxicity synergistically exacerbates LSEC dysfunction in MASLD via IL‐6 trans‐signaling.
Methods: Human adipocytes were treated with palmitic acid (PA). Human LSECs were treated with PA and the IL‐6/soluble IL‐6 receptor (sIL‐6R) complex. Western blotting, qRT‐PCR, RNA sequencing, transwell assays, and immunofluorescence were performed to examine inflammatory responses. MASLD model mice were established using a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) to validate the in vivo results. Alterations in LSEC morphology were examined by western blotting, histology, and electron microscopy.
Results: PA promoted IL‐6 secretion from adipocytes. In LSECs, PA increased NFκB phosphorylation, whereas co‐stimulation with PA and IL‐6/sIL‐6R complex synergistically enhanced activator of transcription 3 (STAT3) phosphorylation and upregulated inflammatory cytokines, chemokines, and adhesion molecules, including VCAM1. Furthermore, RNA sequencing showed concurrent NFκB and Janus kinase (JAK)/STAT pathway activation. This synergistic effect promoted neutrophil migration and VCAM1 expression under in vitro conditions. In the MASLD mouse model, hepatic IL‐6 expression was elevated, accompanied by steatosis, increased transaminase levels, and inflammatory cell infiltration, along with increased VCAM1 expression and sinusoidal capillarization characterized by upregulated CD34 and downregulated CD32b and LYVE‐1.
Conclusion: Lipotoxicity‐amplified IL‐6 trans‐signaling synergistically exacerbates LSEC endotheliopathy and promotes leukocyte recruitment and liver injury, contributing to MASLD progression and providing novel insights into its pathogenesis.
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BibTeX
@article{ueda2026lipotoxicity,
title = {{Lipotoxicity Amplifies IL‐6 Trans‐Signaling in Sinusoidal Endothelial Cells to Promote Endotheliopathy and Liver Injury}},
author = {Yasuhiko Ueda and Nao Kawaguchi and Yosuke Inomata and Jun Arima and Mitsuaki Ishida and Yuko Ito and Sang‐Woong Lee and Kohei Taniguchi},
journal = {Journal of Gastroenterology and Hepatology},
year = {2026},
month = sep,
doi = {10.1111/jgh.70782},
url = {https://doi.org/10.1111/jgh.70782},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Lipotoxicity Amplifies IL‐6 Trans‐Signaling in Sinusoidal Endothelial Cells to Promote Endotheliopathy and Liver Injury
AU - Yasuhiko Ueda
AU - Nao Kawaguchi
AU - Yosuke Inomata
AU - Jun Arima
AU - Mitsuaki Ishida
AU - Yuko Ito
AU - Sang‐Woong Lee
AU - Kohei Taniguchi
PY - 2026
DA - 2026/09/28
JO - Journal of Gastroenterology and Hepatology
DO - 10.1111/jgh.70782
UR - https://doi.org/10.1111/jgh.70782
AB - Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) affects approximately 25% of the global population and is a major health concern. Liver sinusoidal endothelial cells (LSECs) undergo morphological and functional alterations during MASLD progression, resulting in endotheliopathy characterized by pro‐inflammatory phenotypes. We hypothesize that lipotoxicity synergistically exacerbates LSEC dysfunction in MASLD via IL‐6 trans‐signaling. Methods: Human adipocytes were treated with palmitic acid (PA). Human LSECs were treated with PA and the IL‐6/soluble IL‐6 receptor (sIL‐6R) complex. Western blotting, qRT‐PCR, RNA sequencing, transwell assays, and immunofluorescence were performed to examine inflammatory responses. MASLD model mice were established using a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) to validate the in vivo results. Alterations in LSEC morphology were examined by western blotting, histology, and electron microscopy. Results: PA promoted IL‐6 secretion from adipocytes. In LSECs, PA increased NFκB phosphorylation, whereas co‐stimulation with PA and IL‐6/sIL‐6R complex synergistically enhanced activator of transcription 3 (STAT3) phosphorylation and upregulated inflammatory cytokines, chemokines, and adhesion molecules, including VCAM1. Furthermore, RNA sequencing showed concurrent NFκB and Janus kinase (JAK)/STAT pathway activation. This synergistic effect promoted neutrophil migration and VCAM1 expression under in vitro conditions. In the MASLD mouse model, hepatic IL‐6 expression was elevated, accompanied by steatosis, increased transaminase levels, and inflammatory cell infiltration, along with increased VCAM1 expression and sinusoidal capillarization characterized by upregulated CD34 and downregulated CD32b and LYVE‐1. Conclusion: Lipotoxicity‐amplified IL‐6 trans‐signaling synergistically exacerbates LSEC endotheliopathy and promotes leukocyte recruitment and liver injury, contributing to MASLD progression and providing novel insights into its pathogenesis.
SN - 0815-9319
SN - 1440-1746
ER -