Abstract
BackgroundAcute liver failure (ALF) is associated with a high mortality rate, and there are still no effective treatments except liver transplantation and artificial liver therapies. This study aimed to determine the effects, therapeutic window and mechanisms of selonsertib, a selective inhibitor of ASK1, for ALF therapy.ResultsLipopolysaccharide and d-galactosamine (LPS/GalN) were used to simulate ALF. We found that selonsertib pretreatment significantly ameliorated ALF, as determined by reduced hepatic necrosis and serum alanine aminotransferase, aspartate aminotransferase and inflammatory cytokine levels. However, selonsertib is only effective early after LPS/GalN administration, and the limited therapeutic window is related to the activation and mitochondrial translocation of JNK and DRP1. Further experiments revealed that selonsertib could alleviate LPS-induced mitochondrial damage in macrophages by evaluating the mitochondrial membrane potential and mitochondrial permeability transition pore opening in macrophages. Selonsertib also suppressed the release of inflammatory cytokines from macrophages by reducing DRP1-mediated mitochondrial dysfunction, which was confirmed by using mdivi, a specific DRP1 inhibitor.ConclusionsSelonsertib protected against LPS/GalN-induced ALF by attenuating JNK-mediated DRP1 mitochondrial translocation and then rescuing mitochondrial damage in macrophages and may have therapeutic potential for early ALF patients.
Highlights
Acute liver failure (ALF) is a severe consequence of abrupt hepatocyte injury manifested as rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation
LPS/GalN administration induced a remarkable elevation in phosphorylated JNK (p-JNK) levels in liver tissues, while selonsertib pretreatment markedly reduced the phosphorylation of JNK (Fig. 1d)
A Dynamin-related protein 1 (DRP1) inhibitor, we further found that the inhibition of DRP1 activation could effectively inhibit mitochondrial translocation and alleviate LPS-primed abnormal mitochondrial dynamics and mitochondrial dysfunction, which were indicated by the alleviation of the abnormal expression of mitochondrial dynamics-related proteins and the reduction in Mitochondrial permeability transition pore (mPTP) opening and Mitochondrial membrane potential (Δψm) dissipation in LPS-primed macrophages (Fig. 5a, b)
Summary
Acute liver failure (ALF) is a severe consequence of abrupt hepatocyte injury manifested as rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation. Selonsertib, a selective inhibitor of ASK1, has been reported as an effective treatment for non-alcoholic steatohepatitis (NASH) and multidrug resistance (MDR) in various types of cancer in human patients by reducing hepatic steatosis, inflammation and fibrosis or reversing ATP-binding cassette transporter-mediated MDR [8, 9]. Lipopolysaccharide and d-galactosamine (LPS/GalN) are widely used to simulate ALF [11]. The present study aimed to investigate the effects, underlying mechanisms, and therapeutic window of selonsertib in LPS/GalNinduced ALF. Acute liver failure (ALF) is associated with a high mortality rate, and there are still no effective treatments except liver transplantation and artificial liver therapies. This study aimed to determine the effects, therapeutic window and mechanisms of selonsertib, a selective inhibitor of ASK1, for ALF therapy
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