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

Linsey J. F. Peters; Leonida Rakateli; Rosanna Huchzermeier; Andrea Bonnin-Marquez; Sanne Lidewij Maas; Cheng Lin; Alexander Jans; Yana Geng; Alan R. Gorter; Marion J. Gijbels; Sander S. Rensen; Peter Olinga; Tim Hendrikx; Marcin Jan Krawczyk; Malvina Brisbois; Joachim Jankowski; Kiril Bidzhekov; Christian Weber; Erik A.L. Biessen; Ronit Shiri‐Sverdlov; Tom Houben; Yvonne Döring; Matthias Bartneck; Emiel P. C. van der Vorst

doi:10.7554/elife.97165

PathologybioRxivFeb 18, 2024

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

Linsey J. F. Peters iD, Leonida Rakateli, Rosanna Huchzermeier iD, Andrea Bonnin-Marquez iD, Sanne Lidewij Maas iD, Cheng Lin iD, Alexander Jans iD, Yana Geng iD, Alan R. Gorter iD, Marion J. Gijbels iD, Sander S. Rensen iD, Peter Olinga iD, Tim Hendrikx iD, Marcin Jan Krawczyk iD, Malvina Brisbois, Joachim Jankowski iD, Kiril Bidzhekov iD, Christian Weber iD, Erik A.L. Biessen iD, Ronit Shiri‐Sverdlov iD, Tom Houben iD, Yvonne Döring iD, Matthias Bartneck iD, Emiel P. C. van der Vorst iD

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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/fl 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, miR-26b mimic-loaded LNPs were injected in Apoe-/-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-specific miR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in Apoe-/- Mir26b-/- mice. Moreover, Tgfb expression was increased by the miR-26b deficiency, 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 upon miR-26b deficiency, 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 of miR-26b 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/580792v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@b8b5b8org.highwire.dtl.DTLVardef@a26333org.highwire.dtl.DTLVardef@11ed2a0org.highwire.dtl.DTLVardef@963208_HPS_FORMAT_FIGEXP M_FIG C_FIG