Micrornas in metabolism and metabolic diseases

V. Rottiers, Hani Najafi, F. Kristo, S. Gurumurthy, L. Zhong, Y. Li, D. E. Cohen, R. E. Gerszten, N. Bardeesy, R. Mostoslavsky, A. M. Näär

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Abstract

Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the developed world, including metabolic syndrome, type II diabetes, and cardiovascular disease. We have previously uncovered gene regulatory mechanisms of the sterol regulatory element-binding protein (SREBP) family of transcription factors, which control the expression of genes involved in cholesterol and lipid biosynthesis and uptake. Intriguingly, we recently discovered conserved microRNAs (miR-33a/b) embedded within intronic sequences of the human SREBF genes that act in a concerted manner with their host gene products to regulate cholesterol/lipid homeostasis. Indeed, miR-33a/b control the levels of ATP-binding cassette (ABC) transporter ABCA1, a cholesterol efflux pump critical for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport from peripheral tissues. Importantly, antisense inhibition of miR-33 in mice results in elevated HDL and decreased atherosclerosis. Interestingly, miR-33a/b also act in the fatty acid/lipid homeostasis pathway by controlling the fatty acid boxidation genes carnitine O-octanoyltransferase (CROT), hydroxyacyl-coenzyme A-dehydrogenase (HADHB), and carnitine palmitoyltransferase 1A (CPT1A), as well as the energy sensor AMP-activated protein kinase (AMPKa1), the NAD{thorn}-dependent sirtuin SIRT6, and the insulin signaling intermediate IRS2, key regulators of glucose and lipid metabolism. These results have revealed a highly integrated microRNA (miRNA)-host gene circuit governing cholesterol/lipid metabolism and energy homeostasis in mammals that may have important therapeutic implications for the treatment of cardiometabolic disorders.

Original languageEnglish
Pages (from-to)225-233
Number of pages9
JournalCold Spring Harbor Symposia on Quantitative Biology
Volume76
DOIs
Publication statusPublished - 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Rottiers, V., Najafi, H., Kristo, F., Gurumurthy, S., Zhong, L., Li, Y., Cohen, D. E., Gerszten, R. E., Bardeesy, N., Mostoslavsky, R., & Näär, A. M. (2011). Micrornas in metabolism and metabolic diseases. Cold Spring Harbor Symposia on Quantitative Biology, 76, 225-233. https://doi.org/10.1101/sqb.2011.76.011049