MiR-337-3p lowers serum LDL-C level through targeting PCSK9 in hyperlipidemic mice.
Metabolism
; 119: 154768, 2021 06.
Article
em En
| MEDLINE
| ID: mdl-33775647
ABSTRACT
BACKGROUND:
Reducing serum low-density lipoprotein cholesterol (LDL-C) in hyperlipemia is recognized as an effective strategy to minimize the risk of atherosclerotic cardiovascular disease (ASCVD). MiR-337-3p has already been discovered to play regulatory roles in tumor proliferation and metastasis, adipocyte browning and ischemic brain injury, etc. However, the association between miR-337-3p and LDL-C is unknown.METHODS:
Gene Expression Omnibus (GEO) dataset and two hyperlipidemic murine models were used to analyze the potential relationship between miR-337-3p and LDL-C. AAV-mediated liver-directed miRNA overexpression in high fat diet (HFD)-fed mouse model was used to examine the effect of miR-337-3p on LDL-C and WB/RT-PCR/ELISA/luciferase assays were used to investigate the underlying mechanism.RESULTS:
The expressions of miR-337-3p were obviously lower in multiple hyperlipidemic mouse models and had a negative correlation with serum LDL-C levels. After confirming the effect of miR-337-3p on the improvement of serum LDL-C in vivo, we discovered PCSK9 might be a possible target of miR-337-3p, which was further proved by in vitro experiments. MiR-337-3p could directly interact with both the PCSK9 3'UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, the result from DiI-LDL uptake assay under the knockdown of PCSK9 demonstrated that miR-337-3p promoting the absorption of LDL-C in HepG2 cells was dependent on PCSK9, and the result from LDLR-/- mouse model indicated that miR-337-3p regulating LDL-C was dependent on PCSK9/LDLR pathway.CONCLUSION:
We discovered a new function of miR-337-3p in regulating PCSK9 expression and LDL-C absorption, suggesting miR-337-3p might be a new therapeutic target for the development of antihyperlipidemic drug.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
MicroRNAs
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Pró-Proteína Convertase 9
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Hiperlipidemias
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LDL-Colesterol
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article