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bioRxiv · 10.1101/2024.08.08.607275

The ameliorative effect of C-Kit pos hepatic endothelial Mertk deficiency on nonalcoholic steatohepatitis

Fu, S.-W.·Gao, Y.-X.·Li, H.-Y.·Ren, Y.-F.·Wu, J.-C.·Li, Z.-H.·Xu, M.
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Abstract

Recently, Mer tyrosine kinase (Mertk) and KIT proto-oncogene (C-Kit) were reported play a role in liver sinusoidal endothelial cells (LSECs) in patients with nonalcoholic steatohepatitis (NASH). In this study, lower levels of C-Kit and higher levels of Mertk/p-Mertk were confirmed in steatotic LSECs and in the livers of patients and mice with NASH. C-Kit was suggested to negatively regulate Mertk signaling in steatotic LSECs. The steatotic LSECs in which Mertk was knocked down displayed high fenestration and reduced expression of procapillarized CD31/VN; showed antiangiogenic features and decreased expression of proangiogenic VEGF/ERK1/2; and exhibited intact mitophagy and upregulation of the Pink1/Parkin pathway. Bone marrow transplantation (BMT) of C-Kitpos-BMCssh-Mertk to MCD mice could equivalently protect endothelial functions. Steatotic hepatocytes (HCs) or hepatic stellate cells (HSCs) cocultured with LSECssh-Mertk exhibited diminished lipid deposition; decreased expression of prolipogenic LXR/SREBP-1c, proinflammatory TNF-/IL-6 and profibrotic -SMA/ColI; and increased expression of prolipolytic FXR/ADPN. Similarly, the BMT of C-Kitpos-BMCssh-Mertk to MCD mice ameliorated NASH. C-Kitpos-LSECs that underwent Mertk cleavage were found to limit NASH progression. Therefore, Mertk deficiency should be a novel therapeutic agent for restoring LSECs in patients with NASH.

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Fu, S.-W., Gao, Y.-X., Li, H.-Y., Ren, Y.-F., Wu, J.-C., Li, Z.-H., Xu, M.. 2024-08-09. The ameliorative effect of C-Kit pos hepatic endothelial Mertk deficiency on nonalcoholic steatohepatitis. https://doi.org/10.1101/2024.08.08.607275

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