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

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

doi:10.1172/JCI143690

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

Kunimaro Furuta,¹ Qianqian Guo,¹ Kevin D. Pavelko,² Jeong-Heon Lee,³ Keith D. Robertson,⁴ Yasuhiko Nakao,¹ Jan Melek,⁵ Vijay H. Shah,¹ Petra Hirsova,¹ and Samar H. Ibrahim⁶

Published January 21, 2021 - More info

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Abstract

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSEC) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that vascular cell adhesion molecule 1 (VCAM-1) mediates monocyte adhesion to LSEC. 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, mixed lineage kinase 3 (MLK3). Likewise, LSEC-VCAM-1 expression was reduced in the Mlk3^-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing antibody 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.

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

Kunimaro Furuta,¹ Qianqian Guo,¹ Kevin D. Pavelko,² Jeong-Heon Lee,³ Keith D. Robertson,⁴ Yasuhiko Nakao,¹ Jan Melek,⁵ Vijay H. Shah,¹ Petra Hirsova,¹ and Samar H. Ibrahim⁶

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

Kunimaro Furuta,1 Qianqian Guo,1 Kevin D. Pavelko,2 Jeong-Heon Lee,3 Keith D. Robertson,4 Yasuhiko Nakao,1 Jan Melek,5 Vijay H. Shah,1 Petra Hirsova,1 and Samar H. Ibrahim6

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Kunimaro Furuta,¹ Qianqian Guo,¹ Kevin D. Pavelko,² Jeong-Heon Lee,³ Keith D. Robertson,⁴ Yasuhiko Nakao,¹ Jan Melek,⁵ Vijay H. Shah,¹ Petra Hirsova,¹ and Samar H. Ibrahim⁶