Mertk+ Liver Sinusoidal Endothelial Cells Negatively Regulate PINK1 Related Mitophagy and Accelerate MASH

Background: Mer tyrosine kinase (Mertk) regulating mitochondrial function of liver sinusoidal endothelial cells (LSECs) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear.

Methods: Mertk/p-Mertk, PINK1, and ERK/p-ERK expression in steatotic LSECs and livers of MASH mice were studied. Mitochondrial functions were assessed via immunofluorescence, Western blot, and qPCR. c-Kit⁺-bone marrow cells (BMCs)^sh-Mertk were bone marrow transplanted (BMT) to MASH mice to evaluate its effect.

Results: Ov-Mertk would markedly stimulate ERK, and ERK further suppress downstream PINK1. Higher levels of Mertk/p-Mertk and lower levels of PINK1 were confirmed in steatotic LSECs and MASH mice livers. Steatotic LSECs^sh-Mertk exhibited intact Mitophagy, integral mitochondrial membrane potential, reduced reactive oxygen productions and upregulation of the PINK1 pathway. BMT of c-Kit⁺-BMCs^sh-Mertk could equivalently protect mitochondrial functions and ameliorate lipid accumulation in MASH mice.

Conclusion: Mertk negatively regulates PINK1-mediated Mitophagy in LSECs through the p-ERK signaling pathway, thereby accelerating MASH progression. Therefore, LSECs deficient of Mertk should be a novel therapy for reversing PINK1-related Mitophagy and MASH.

Mer tyrosine kinase (Mertk); PTEN‐induced putative kinase 1 (PINK1); extracellular regulated protein kinase (ERK); liver sinusoidal endothelial cell (LSEC); metabolic dysfunction‐associated steatohepatitis (MASH); mitophagy.