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Atherosclerosis. 2015 Dec;243(2):499-509. doi: 10.1016/j.atherosclerosis.2015.09.033.

miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice.

Author information

1
Section of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA.
2
Edward A. Doisy Department of Biochemistry and Molecular Biology, Center for Cardiovascular Research, Saint Louis University School of Medicine, Saint Louis, MO, USA.
3
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
4
Section of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: carlos.fernandez@yale.edu.

Abstract

RATIONALE:

Recently, there has been significant interest in the therapeutic administration of miRNA mimics and inhibitors to treat cardiovascular disease. In particular, miR-27b has emerged as a regulatory hub in cholesterol and lipid metabolism and potential therapeutic target for treating atherosclerosis. Despite this, the impact of miR-27b on lipid levels in vivo remains to be determined. As such, here we set out to further characterize the role of miR-27b in regulating cholesterol metabolism in vitro and to determine the effect of miR-27b overexpression and inhibition on circulating and hepatic lipids in mice.

METHODS AND RESULTS:

Our results identify miR-27b as an important regulator of LDLR activity in human and mouse hepatic cells through direct targeting of LDLR and LDLRAP1. In addition, we report that modulation of miR-27b expression affects ABCA1 protein levels and cellular cholesterol efflux to ApoA1 in human hepatic Huh7 cells. Overexpression of pre-miR-27b in the livers of wild-type mice using AAV8 vectors increased pre-miR-27b levels 50-fold and reduced hepatic ABCA1 and LDLR expression by 50% and 20%, respectively, without changing circulating and hepatic cholesterol and triglycerides. To determine the effect of endogenous miR-27b on circulating lipids, wild-type mice were fed a Western diet for one month and injected with 5 mg/kg of LNA control or LNA anti-miR-27b oligonucleotides. Following two weeks of treatment, the expression of ABCA1 and LDLR were increased by 10-20% in the liver, demonstrating effective inhibition of miR-27b function. Intriguingly, no differences in circulating and hepatic lipids were observed between treatment groups.

CONCLUSIONS:

The results presented here provide evidence that short-term modulation of miR-27b expression in wild-type mice regulates hepatic LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels.

KEYWORDS:

ABCA1; Atherosclerosis; LDLR; Lipid homeostasis; miR-27b; miRNAs

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