miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling

Alberto Dávalos, Leigh Goedeke, Peter Smibert, Cristina M. Ramírez, Nikhil P. Warrier, Ursula Andreo, Daniel Cirera-Salinas, Katey Rayner, Uthra Suresh, José Carlos Pastor-Pareja, Enric Esplugues, Edward A. Fisher, Luiz O.F. Penalva, Kathryn J. Moore, Yajaira Suárez, Eric C. Lai, Carlos Fernández-Hernando

Research output: Contribution to journalArticle

421 Scopus citations

Abstract

Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.

Original languageEnglish (US)
Pages (from-to)9232-9237
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number22
DOIs
StatePublished - May 31 2011

Keywords

  • Cardiovascular disease
  • Lipid homeostasis
  • Posttranscriptional regulation

ASJC Scopus subject areas

  • General

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    Dávalos, A., Goedeke, L., Smibert, P., Ramírez, C. M., Warrier, N. P., Andreo, U., Cirera-Salinas, D., Rayner, K., Suresh, U., Pastor-Pareja, J. C., Esplugues, E., Fisher, E. A., Penalva, L. O. F., Moore, K. J., Suárez, Y., Lai, E. C., & Fernández-Hernando, C. (2011). miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proceedings of the National Academy of Sciences of the United States of America, 108(22), 9232-9237. https://doi.org/10.1073/pnas.1102281108