Goedeke, LeighRotllan, NoemiCanfrán-Duque, AlbertoAranda, Juan F.Ramírez, Cristina M.Araldi, ElisaLin, Chin-ShengAnderson, Norma N.Wagschal, Alexandrede Cabo, RafaelHorton, Jay D.Lasunción, Miguel A.Naar, AndersSuárez, YajairaFernández-Hernando, Carlos2016-06-142015Goedeke, L., N. Rotllan, A. Canfrán-Duque, J. F. Aranda, C. M. Ramírez, E. Araldi, C. Lin, et al. 2015. “Identification of miR-148a as a novel regulator of cholesterol metabolism.” Nature medicine 21 (11): 1280-1289. doi:10.1038/nm.3949. http://dx.doi.org/10.1038/nm.3949.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320238The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL-cholesterol (LDL-C). While the transcriptional regulation of LDLR is well-characterized, the post-transcriptional mechanisms which govern LDLR expression are just beginning to emerge. Here, we developed a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen, we characterize miR-148a as a negative regulator of LDLR expression and activity, and define a novel SREBP1-mediated pathway by which miR-148a regulates LDL-C uptake. Importantly, inhibition of miR-148a increases hepatic LDLR expression and decreases plasma LDL-C in vivo. We also provide evidence that miR-148a regulates hepatic ABCA1 expression and circulating HDL-C levels. Collectively, these studies uncover miR-148a as an important regulator of hepatic LDL-C clearance through direct regulation of LDLR expression, and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate the elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.en-USJournal Article2016-06-1410.1038/nm.3949