MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels

Nat Med. 2015 Nov;21(11):1280-9. doi: 10.1038/nm.3949. Epub 2015 Oct 5.


The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL cholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, the post-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here we develop a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen we identified and characterized miR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatory element-binding protein 1 (SREBP1)-mediated pathway through which miR-148a regulates LDL-C uptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C. Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A, member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. These studies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics*
  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Cholesterol, HDL / metabolism*
  • Cholesterol, LDL / metabolism*
  • Gene Expression Regulation
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • High-Throughput Screening Assays
  • Humans
  • Liver / metabolism*
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • RNA Processing, Post-Transcriptional
  • Receptors, LDL / genetics*
  • Receptors, LDL / metabolism
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism


  • ATP Binding Cassette Transporter 1
  • Cholesterol, HDL
  • Cholesterol, LDL
  • MIRN148 microRNA, human
  • MicroRNAs
  • Receptors, LDL
  • Sterol Regulatory Element Binding Protein 1