Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis
Kunimaro Furuta, … , Petra Hirsova, Samar H. Ibrahim
Kunimaro Furuta, … , Petra Hirsova, Samar H. Ibrahim
Published January 21, 2021
Citation Information: J Clin Invest. 2021;131(6):e143690. https://doi.org/10.1172/JCI143690.
View: Text | PDF
Research Article Hepatology Article has an altmetric score of 8

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

Abstract

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.

Authors

Kunimaro Furuta, Qianqian Guo, Kevin D. Pavelko, Jeong-Heon Lee, Keith D. Robertson, Yasuhiko Nakao, Jan Melek, Vijay H. Shah, Petra Hirsova, Samar H. Ibrahim

×

Figure 4

VCAM-1 is upregulated in LSECs under lipotoxic conditions via a MAPK pathway.

Options: View larger image (or click on image) Download as PowerPoint
VCAM-1 is upregulated in LSECs under lipotoxic conditions via a MAPK pat...
(A) Primary mouse LSECs were treated with vehicle (Veh) or 250 μM of PA for 16 hours. (B) Primary human LSECs were treated with vehicle or 500 μM of PA for 16 hours. The mRNA expression levels of Vcam1 were evaluated by real-time qPCR. FC was determined after normalization to 18S rRNA expression and expressed as FC to that observed in vehicle-treated cells. (C) Primary human LSECs were treated with 500 μM of PA. Protein levels of VCAM-1, phosphorylated and total MKK3/6, and p38 were assessed by Western blot. GAPDH was used as a loading control. (D) Schematic representation of the MAPK pathway and its inhibitors. (E) Primary mouse LSECs were treated with 250 μM of PA ± 2 μM of the MLK3 inhibitor URMC-099 (URMC) for 16 hours. (F) Primary human LSECs were treated with 500 μM of PA ± 2 μM of URMC or 10 μM of p38 inhibitor SB203580 (SB) or 20 μM of the JNK inhibitor SP600125 (SP) for 16 hours. The mRNA expression levels of Vcam1 were evaluated by real-time qPCR. (G) Eight-week-old WT C57BL/6J mice (WT) or mice with whole body Mlk3 knockout (Mlk3–/–) were fed either chow or FFC diet for 24 weeks to induce NASH. Representative images of VCAM-1 immunostaining of liver tissue sections are shown. Scale bars: 100 μm. VCAM-1–positive areas were quantified in 5 random ×10 microscopic fields and averaged for each animal (n = 3 per group). Graphs represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, unpaired t test and 1-way ANOVA with Bonferroni’s multiple comparison.