MicroRNA-26b protects against MASH development and can be efficiently targeted with lipid nanoparticles

Abstract

Background & AimsThe prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (miR-26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of miR-26b in MASH and its therapeutic potential using miR-26b mimic-loaded lipid nanoparticles (LNPs).MethodsApoe-/-Mir26b-/-,Apoe-/-LysMcreMir26bfl/flmice, and respective controls were fed a western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, miR-26b mimic-loaded LNPs were injected inApoe-/-Mir26b-/-mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms.ResultsApoe-/-Mir26b-/-mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specificmiR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased inApoe-/-Mir26b-/-mice. Moreover,Tgfbexpression was increased by themiR-26bdeficiency, leading to more hepatic fibrosis. A murine treatment model with miR-26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling uponmiR-26bdeficiency, which was rescued by LNP treatment. Finally, miR-26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices.ConclusionsOverall, our study demonstrates that the detrimental effects ofmiR-26bdeficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology.Graphical abstract