TMAO upregulates members of the miR-17/92 cluster and impacts targets associated with atherosclerosis

Authors: DIEZ-RICOTE, LAURA - Imdea Institute; RUIZ-VALDERREY, PALOMA - Imdea Institute; MICO, VICTOR - Imdea Institute; BLANCO, RUTH - Imdea Institute; TOME-CARNEIRO, JOAO - Imdea Institute; DAVALOS, ALBERTO - Imdea Institute; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DAIMIEL, LIDIA - Imdea Institute

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/8/2022
Publication Date: 10/11/2022
Citation: Diez-Ricote, L., Ruiz-Valderrey, P., Mico, V., Blanco, R., Tome-Carneiro, J., Davalos, A., Ordovas, J.M., Daimiel, L. 2022. TMAO upregulates members of the miR-17/92 cluster and impacts targets associated with atherosclerosis. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms232012107.
DOI: https://doi.org/10.3390/ijms232012107

Interpretive Summary: Trimethylamine N-oxide (TMAO) is a dietary byproduct formed by gut bacteria during digestion. It is derived partly from nutrients abundant in red meat. While high saturated fat levels in red meat have long been known to contribute to heart disease, many studies have identified TMAO as another culprit. Until now, little is known about the mechanisms by which TMAO may contribute to that increased heart disease risk. We conducted a cell study to investigate the effects of TMAO on the regulation of gene expression mediated by microRNAs (a family of small RNA molecules that helps cells control the kinds and amounts of proteins they make). Our results show that TMAO modulates the expression of a family of microRNAs and that such modulation could promote inflammation and blood clotting, ultimately promoting atherosclerosis and CVD. This information increases our understanding of the relationship between the consumption of animal products and increased heart disease risk.

Technical Abstract: Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 microM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD.