View in EDS

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

Saved in:
Bibliographic Details
Title: MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles
Authors: Leonida Rakateli, Linsey Peters, Rosanna Huchzermeier, Andrea Bonnin-Marquez, Sanne L Maas, Cheng Lin, Alexander Jans, Yana Geng, Alan Gorter, Marion Gijbels, Sander Rensen, Peter Olinga, Tim Hendrikx, Marcin Krawczyk, Malvina Brisbois, Joachim Jankowski, Kiril Bidzhekov, Christian Weber, Erik AL Biessen, Ronit Shiri-Sverdlov, Tom Houben, Yvonne Döring, Matthias Bartneck, Emiel van der Vorst
Source: eLife
eLife, Vol 13 (2025)
Publisher Information: eLife Sciences Publications, Ltd, 2024.
Publication Year: 2024
Subject Terms: Male, QH301-705.5, Knockout, Science, Fatty Liver/prevention & control genetics, lipid nanoparticles, immunology, Mice, Immunology and Inflammation, Apolipoproteins E, Liver/pathology metabolism, Nanoparticles/administration & dosage chemistry, Animals, Humans, human, Biology (General), mouse, Mice, Knockout, hepatic inflammation, Animal, MicroRNAs/genetics metabolism, Lipid Metabolism, microRNAs, Fatty Liver, MicroRNAs, Disease Models, Animal, metabolic dysfunction-associated steatohepatitis, Liver, inflammation, Disease Models, Liposomes, Medicine, Nanoparticles, Apolipoproteins E/genetics
Description: 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/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. 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-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. Conclusions Overall, 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.
Document Type: Article
Other literature type
ISSN: 2050-084X
DOI: 10.7554/elife.97165.2
DOI: 10.1101/2024.02.18.580792
DOI: 10.7554/elife.97165
DOI: 10.7554/elife.97165.3
DOI: 10.48620/88095
Access URL: https://pubmed.ncbi.nlm.nih.gov/40261813
https://doaj.org/article/fc05e0d77f5f47429f535551ad4b70b7
https://cris.maastrichtuniversity.nl/en/publications/ad7a196d-5e6c-46c9-a15c-baa7aadc1b7e
https://doi.org/10.7554/eLife.97165
https://epub.ub.uni-muenchen.de/126056/
Rights: CC BY
URL: https://www.biorxiv.org/about/FAQ#license
Accession Number: edsair.doi.dedup.....2c9378f7dffdf47360e8e67789ca9be7
Database: OpenAIRE
Description
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/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. 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-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. Conclusions Overall, 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.
ISSN:2050084X
DOI:10.7554/elife.97165.2