MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles
The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b ( Mir26b ) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of Mir26b in MASH and its therapeutic potential using Mir26b mimic-loaded lipid nanoparticles (LNPs). Apoe -/- Mir26b -/- , Apoe -/- Lyz2 cre Mir26b fl/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, Mir26b 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. Apoe -/- 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 Mir26b . 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 Mir26b deficiency, leading to more hepatic fibrosis. A murine treatment model with Mir26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon Mir26b deficiency, which was rescued by LNP treatment. Finally, Mir26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. Overall, our study demonstrates that the detrimental effects of Mir26b 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.
Authors
- Yvonne Doering
- Linsey J. F. Peters (ORCID: https://orcid.org/0009-0009-3657-9441)
- Erik A.L. Biessen (ORCID: https://orcid.org/0000-0002-6454-8548)
- Marcin Krawczyk (ORCID: https://orcid.org/0000-0002-0113-0777)
- Marion J. Gijbels (ORCID: https://orcid.org/0000-0002-4906-0384)
- Alexander Jans (ORCID: https://orcid.org/0000-0002-2622-4278)
- Peter Olinga (ORCID: https://orcid.org/0000-0003-4855-8452)
- Emiel P. C. van der Vorst (ORCID: https://orcid.org/0000-0001-5771-6278)
- Kiril Bidzhekov
- Cheng Lin (ORCID: https://orcid.org/0009-0007-2326-1536)
- Matthias Bartneck (ORCID: https://orcid.org/0000-0003-1516-9610)
- Andrea Bonnin-Marquez
- Sander S. Rensen (ORCID: https://orcid.org/0000-0001-5054-8400)
- Sanne L. Maas (ORCID: https://orcid.org/0000-0003-1423-8901)
- Yana Geng (ORCID: https://orcid.org/0000-0003-1529-0875)
- Joachim Jankowski (ORCID: https://orcid.org/0000-0002-4528-2967)
- Ronit Shiri‐Sverdlov (ORCID: https://orcid.org/0000-0002-6736-7814)
- Tom Houben (ORCID: https://orcid.org/0000-0002-0441-3166)
- Tim Hendrikx (ORCID: https://orcid.org/0000-0002-3381-2107)
- Leonida Rakateli
- Rosanna Huchzermeier
- Malvina Brisbois
- Christian Weber (ORCID: https://orcid.org/0000-0003-4610-8714)
- Alan Gorter (ORCID: https://orcid.org/0009-0000-6331-6705)
Institutions
- University of Bern (CH)
- University of Groningen (NL)
- University Hospital of Bern (CH)
- University Medical Center (US)
- Cardiovascular Institute Hospital (JP)
- Maastricht University (NL)
- Institute of Rheumatology (CZ)
- DWI – Leibniz Institute for Interactive Materials (DE)
- Munich Cluster for Systems Neurology (DE)
- Universitätsklinikum Aachen (DE)
- German Centre for Cardiovascular Research (DE)
- Amsterdam University Medical Centers (NL)
- Medical University of Vienna (AT)
- Ludwig-Maximilians-Universität München (DE)
- University of Amsterdam (NL)
- RWTH Aachen University (DE)
- Saarland University (DE)
Publication Details
- Journal
- eLife
- Published
- 2025-04-22
- DOI
- https://doi.org/10.7554/elife.97165.3
- Citations
- 1
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Wilhelm Sander-Stiftung
- Corona-Stiftung
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Bundesministerium für Bildung und Forschung
- Fritz Thyssen Stiftung
- China Scholarship Council
- RWTH Aachen University