MicroRNA-26b protects against MASH development and can be efficiently targeted with lipid nanoparticles
Abstract Background & Aims The 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).Methods Apoe-/-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.Results 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-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.Conclusions Overall, 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 <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="580792v1_ufig1" position="float" orientation="portrait" /></jats:fig>.
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 27. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Peters, Linsey J.F. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.18.580792 |
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| PPN (Katalog-ID): |
XBI042643236 |
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| 520 | |a Abstract Background & Aims The 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).Methods Apoe-/-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.Results 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-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.Conclusions Overall, 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 <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="580792v1_ufig1" position="float" orientation="portrait" /></jats:fig> | ||
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| 700 | 1 | |a Bonnin-Marquez, Andrea |4 aut | |
| 700 | 1 | |a Maas, Sanne L. |4 aut | |
| 700 | 1 | |a Lin, Cheng |4 aut | |
| 700 | 1 | |a Jans, Alexander |4 aut | |
| 700 | 1 | |a Geng, Yana |4 aut | |
| 700 | 1 | |a Gorter, Alan |4 aut | |
| 700 | 1 | |a Gijbels, Marion J. |4 aut | |
| 700 | 1 | |a Rensen, Sander S. |4 aut | |
| 700 | 1 | |a Olinga, Peter |4 aut | |
| 700 | 1 | |a Hendrikx, Tim |4 aut | |
| 700 | 1 | |a Krawczyk, Marcin |4 aut | |
| 700 | 1 | |a Brisbois, Malvina |4 aut | |
| 700 | 1 | |a Jankowski, Joachim |4 aut | |
| 700 | 1 | |a Bidzhekov, Kiril |4 aut | |
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| 700 | 1 | |a Shiri-Sverdlov, Ronit |4 aut | |
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| 700 | 1 | |a van der Vorst, Emiel P.C. |0 (orcid)0000-0001-5771-6278 |4 aut | |
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