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) 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 exhibited intact mitophagy, integral mitochondrial membrane potential, reduced reactive oxygen productions and upregulation of the PINK1 pathway. BMT of C-Kit-BMCs 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.