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 (<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<sup>-/-</sup>Mir26b<sup>-/-</sup></i>, <i>Apoe<sup>-/-</sup>Lyz2<sup>cre</sup>Mir26b<sup>fl/fl</sup></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<sup>-/-</sup>Mir26b<sup>-/-</sup></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<sup>-/-</sup>Mir26b<sup>-/-</sup></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<sup>-/-</sup>Mir26b<sup>-/-</sup></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.
Authors
- 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
- Yvonne Döring (ORCID: https://orcid.org/0000-0001-9307-3396)
- 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)
- Center for Clinical Research (United States) (US)
- 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
- 2024-08-05
- DOI
- https://doi.org/10.7554/elife.97165
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- ZonMw
- Bundesministerium für Bildung und Forschung
- China Scholarship Council