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

Abstract

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (<i>Mir26b</i>) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of <i>Mir26b</i> in MASH and its therapeutic potential using <i>Mir26b</i> mimic-loaded lipid nanoparticles (LNPs). <i>Apoe^-/-Mir26b^-/-</i>, <i>Apoe^-/-Lyz2^creMir26b^fl/fl</i> mice, 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, <i>Mir26b</i> mimic-loaded LNPs were injected in <i>Apoe^-/-Mir26b^-/-</i> 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. <i>Apoe^-/-Mir26b^-/-</i> 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-specific <i>Mir26b</i>. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in <i>Apoe^-/-Mir26b^-/-</i> mice. Moreover, <i>Tgfb</i> expression was increased by the <i>Mir26b</i> deficiency, leading to more hepatic fibrosis. A murine treatment model with <i>Mir26b</i> mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon <i>Mir26b</i> deficiency, which was rescued by LNP treatment. Finally, <i>Mir26b</i> mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. Overall, our study demonstrates that the detrimental effects of <i>Mir26b</i> deficiency 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.