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.
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Research Article Hepatology

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

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Figure 2

Genome-wide studies identified transcriptional upregulation of Vcam1 in LSECs in murine NASH.

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Genome-wide studies identified transcriptional upregulation of Vcam1 in ...
(A) Schematic diagram of the transcriptome and open chromatin landscape study on LSECs. (B) Heatmaps of read densities within ± 1.5 kb of peak centers of the top 500 differential accessible regions (DARs) with the lowest FDR between chow-fed (n = 3) and FFC-fed (n = 4) mice. The graphs at the top represent the normalized read densities of the same 500 differential accessible regions. (C) Genome browser track of ATAC-Seq read signal intensities in the region close to Vcam1 locus. The red box indicates a genomic region with differential signal intensity between the conditions. (D) Volcano plot of genes associated with OCRs using LSECs of chow- vs. FFC-fed mice. Gray dots represent the nearest genes from detected OCRs located between –1 kb and +0.1 kb from the TSSs. The x and y axes represent log2 FC and –log10 converted P value (-log10p) of read coverage signals in FFC- versus chow-fed mice, respectively. Dots in the blue area represent genes that passed the threshold of log2 FC > 1 and –log10 P < 2. The black dot represents Vcam1. (E) Volcano plot of genes assessed by RNA-Seq of LSECs from chow- vs. FFC-fed mice. Dots in the pink area represent genes that passed the threshold of log2 FC > 0.9 and –log10 P < 17. (F) Venn diagram of the genes that passed the thresholds above extracted by ATAC-Seq and RNA-Seq using LSEC chow- vs. FFC-fed mice.