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microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator

Jiang, Huajun, Zhang, Jin, Du, Yu, Jia, Xiaojian, Yang, Fan, Si, Shuyi, Wang, Li, Hong, Bin·2015·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2015.10.026
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Abstract

Objective Low-density lipoprotein receptor (LDLR) mediates endocytosis of LDL particles and is important in maintaining plasma cholesterol levels, thus its expression is under extensive regulation at multiple levels, including transcriptional and posttranscriptional regulation by transcription factors (TFs) and RNA-binding proteins (RBPs). Here, we identified microRNA-185 (miR-185) as a novel direct posttranscriptional regulator of LDLR and an indirect LDLR modulator through KSRP in hepatic cells. Methods and results Using quantitative real-time PCR (qPCR), we detected the effect of predicted LDLR-targeting miRNAs and found that overexpression of miR-185 repressed LDLR expression and LDL uptake in HepG2 cells by 62.4 ± 6.0% (p = 7.0 × 10(-5)) and 32.5 ± 6.0% (p = 7.7 × 10(-4)) respectively, through directly targeting LDLR 3'UTR. Unexpectedly, the antisense inhibitor of miR-185 had similar repression effect on LDLR although it reduced the association of endogenous miR-185 with LDLR mRNA. Further experiments revealed that KH-type splicing regulatory protein (KSRP), one of the LDLR-destabilizing RBPs, is also a target of miR-185. KSRP silencing reversed the repression effects of miR-185-inhibitor on LDLR. Thus miR-185 regulates LDLR expression not only through directly targeting but also by a RBP-involved indirect pathway. Finally, the in vivo results showed that miR-185-inhibitor upregulated hepatic LDLR expression and correlated with a decrease in plasma cholesterol level and…

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  • Numerous miRNAs directly bind LDLR mRNA 3′UTR and decrease its expression, including miR-27a, miR-27b, miR-128-1, miR-128-3p, miR-130b, miR-148a, miR-184a, miR-185, and miR-301b.

    “Numerous miRNAs have been shown to directly bind LDLR mRNA 3' UTR and decrease its expression (Fig. 2), including miR-27a, miR-27b, miR-128-1, miR-128-3p, miR-130b, miR-148a, miR-184a, miR-185, and miR-301b [43][44][45][46][47][48].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [47]

  • Inhibition of miR-185 in APOE-knockout mice increases LDLR abundance, reduces plasma cholesterol, and attenuates atherosclerotic plaque formation.

    “Similarly, inhibition of miR-185 in APOE-knockout mice increases LDLR abundance, reduces plasma cholesterol, and attenuates atherosclerotic plaque formation [47]”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [47]

  • miR-27a, miR-27b, miR-128-1, miR-128-3p, miR-130b, miR-148a, miR-184a, miR-185, and miR-301b inhibit expression of the LDLR, decreasing LDLR.

    “miR-27a, miR-27b, miR-128-1, miR-128-3p, miR-130b, miR-148a, miR-184a, miR-185, miR-301b Inhibit expression of the LDLR ↓ [43-48]”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [47]

  • Luciferase reporter assays involving mutations of the miR-185 binding sites in the LDLR 3'UTR stabilized luciferase expression, suggesting miR-185 regulation of LDLR at these binding sites.

    “Additionally, luciferase reporter assays involving mutations of the miR-185 binding sites in the LDLR 3’UTR stabilized the luciferase expression, suggesting miR-185 regulation of LDLR at these binding sites54.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [54]

  • Overexpression of miR-185 in HepG2 cells resulted in decreased expression of LDLR mRNA and protein and decreased LDL uptake.

    “Overexpression of miR-185 in HepG2 cells resulted in decreased expression of LDLR mRNA and protein and decreased LDL uptake54.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [54]

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Metadata

Authors
Jiang, H., Zhang, J., Du, Y., Jia, X., Yang, F., Si, S., Wang, L., & Hong, B.
ORCID
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2015-12
Volume
243
Issue
2
Pages
523-532
ISSN
0021-9150
DOI
10.1016/j.atherosclerosis.2015.10.026
Cited by
70
References
4
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Funders
  • National Natural Science Foundation of China (81473214, 81102442, 90813027)
  • National Mega-project for Innovative Drugs (2012ZX09301002-003)

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