MicroRNA-26b as novel regulator of cardio-metabolic diseases

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): IZKF Increasing evidence has shown that microRNAs (miRs) are fundamental players in cardio-metabolic diseases. MiR-26b has been associated with the development of metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis, although causality has not been demonstrated yet. Therefore, we aimed to determine the causal role of miR-26b in MASH and atherosclerosis. Apoe-/-Mir-26b-/- mice were fed a 4- or 12-week western type diet (WTD). Plasma and liver samples were subjected to various assays to investigate the effects on lipid metabolism, inflammation and fibrosis. Additionally, miR-26b mimic-loaded lipid nanoparticles (LNPs) were used to rescue the phenotype. A 1.5-fold increase in hepatic lipid levels was observed in Apoe-/-Mir26b-/- mice, while plasma cholesterol/triglyceride levels remained unchanged. These results were further confirmed by an increase in steatosis. Additionally, the proinflammatory cytokines TNF-α, IL-6 and CXCL1 were significantly elevated, which coincided with increased macrophage infiltration into the liver. Moreover, loss of miR-26b resulted in more hepatic fibrosis. Finally, a treatment with miR-26b mimic-loaded LNPs reduced hepatic lipid levels, rescuing the observed phenotype. Additionally, Apoe-/-Mir26b-/- mice demonstrated a striking 10-fold increase in atherosclerotic lesion size. Consistent with a more advanced plaque phenotype, collagen content and relative necrotic core area were significantly increased in plaques from mice lacking miR-26b. Intriguingly, this increased atherosclerotic lesion size could also be rescued by repetitive injections of miR-26b mimic-loaded LNPs. Overall, our results demonstrate a protective role of miR-26b in cardio-metabolic diseases, thereby opening doors to future research and potential new treatment options using LNP technology.