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

Leigh Goedeke, Noemi Rotllan, Alberto Canfrán-Duque, Juan F. Aranda, Cristina M. Ramírez, Elisa Araldi, Chin Sheng Lin, Norma N. Anderson, Alexandre Wagschal, Rafael De Cabo, Jay D. Horton, Miguel A. Lasunción, Anders M. Näär, Yajaira Suárez, Carlos Fernández-Hernando

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1280-1288
Number of pages9
JournalNature medicine
Volume21
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Goedeke, L., Rotllan, N., Canfrán-Duque, A., Aranda, J. F., Ramírez, C. M., Araldi, E., Lin, C. S., Anderson, N. N., Wagschal, A., De Cabo, R., Horton, J. D., Lasunción, M. A., Näär, A. M., Suárez, Y., & Fernández-Hernando, C. (2015). MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nature medicine, 21(11), 1280-1288. https://doi.org/10.1038/nm.3949