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

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-Kit ^pos -BMCs ^sh-Mertk to MCD mice could equivalently protect endothelial functions. Steatotic hepatocytes (HCs) or hepatic stellate cells (HSCs) cocultured with LSECs ^sh-Mertk exhibited diminished lipid deposition; decreased expression of prolipogenic LXR/SREBP-1c, proinflammatory TNF-α/IL-6 and profibrotic α-SMA/ColI; and increased expression of prolipolytic FXR/ADPN. Similarly, the BMT of C-Kit ^pos -BMCs ^sh-Mertk to MCD mice ameliorated NASH. C-Kit ^pos -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.