MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis

Science. 2010 Jun 18;328(5985):1566-9. doi: 10.1126/science.1189123. Epub 2010 May 13.

Abstract

Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. The sterol regulatory element-binding proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. We show here that microRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate-binding cassette transporter A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional repression. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid-antisense oligonucleotides results in elevated plasma HDL. Our findings indicate that miR-33 acts in concert with the SREBP host genes to control cholesterol homeostasis and suggest that miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Cell Line
  • Cholesterol / metabolism*
  • Cholesterol, HDL / blood*
  • Diet
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Introns
  • Liver / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oligonucleotides, Antisense / pharmacology
  • RNA Interference
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Sterol Regulatory Element Binding Proteins / genetics*
  • Sterol Regulatory Element Binding Proteins / metabolism
  • Up-Regulation

Substances

  • 3' Untranslated Regions
  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Cholesterol, HDL
  • MIRN33a microRNA, human
  • MicroRNAs
  • Mirn33 microRNA, mouse
  • Oligonucleotides, Antisense
  • SREBF1 protein, human
  • SREBF2 protein, human
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Sterol Regulatory Element Binding Proteins
  • Cholesterol