miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice
- Goedeke, Leigh
- Rotllan, Noemi
- Ramírez, Cristina M.
- Aranda, Juan F.
- Canfrán-Duque, Alberto
- Araldi, Elisa
- Fernández-Hernando, Ana
- Langhi, Cedric
- de Cabo, Rafael
- Baldán, Ángel
- Suárez, Yajaira
- Fernández-Hernando, Carlos
ISSN: 0021-9150
Año de publicación: 2015
Volumen: 243
Número: 2
Páginas: 499-509
Tipo: Artículo
Otras publicaciones en: Atherosclerosis
Resumen
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.
Información de financiación
Financiadores
-
National Institutes of Health
- R01HL107953
- R01HL107953-04S1
- R01HL106063
- R01HL105945
- 1F31AG043318
- R01HL107794
-
American Heart Association
- 15SDG23000025
- GRNT20460189
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