The ameliorative effect of C-Kit+ hepatic endothelial cells with 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). The exact mechanism of Mertk was explored involving C-Kit+-LSECs in 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/vitronectin; showed antiangiogenic features and decreased expression of proangiogenic VEGF; and exhibited inhibiting proliferation, migration and vasodilation. Bone marrow transplantation (BMT) of C-Kit+-ECssh-Mertk (endothelial cells with Mertk deficiency) to NASH mice could equivalently protect endothelial functions. Steatotic hepatocytes or hepatic stellate cells cocultured with LSECssh-Mertk exhibited diminished lipid deposition; decreased expression of prolipogenic LXR/SREBP-1c, proinflammatory TNF-α/IL-6, and profibrotic α-SMA/ColI/TGFβ1; increased expression of prolipolytic FXR/ADPN; and facilitated proliferation and apoptosis. Similarly, BMT of C-Kit+-ECssh-Mertk to NASH mice could ameliorate the disease outcome. C-Kit+-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.