MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins
Open accessAbstract
Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. Reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of messenger RNA reporters. Furthermore, HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be dependent on scavenger receptor class B type I. The human HDL-miRNA profile of normal subjects is significantly different from that of familial hypercholesterolemia subjects. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations indicate that HDL participates in a mechanism of intercellular communication involving the transport and delivery of miRNAs.
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HDL transports proteins, hormones, carotenoids, vitamins, bioactive lipids, and 90% of extracellular miRNA, and a reduction in HDL levels leads to reduced miRNA and changes in gene expression.
“HDL also transports proteins, hormones, carotenoids, vitamins, bioactive lipids, and 90% of extracellular micro-ribonucleic acids (miRNA), and a reduction in HDL levels leads to reduced miRNA and changes in gene expression [5].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [5]
The Discussion (page not provided) states that HDL transports miRNAs and that HDL-mediated delivery can alter gene expression in recipient cells. It also describes HDL as carrying lipids and proteins, but our copy does not substantiate the full list of other cargo, the claim that HDL carries 90% of extracellular miRNA, or the proposed effect of reduced HDL levels. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe lower adaptive impairment detected in the HDL <5thCent group might be related to decreased amounts of circulating miRNA.
“the lower adaptive impairment detected in the HDL <5thCent group might be related to decreased amounts of circulating miRNA.”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [5]
The Discussion (page unavailable) describes HDL as a possible carrier of circulating miRNAs, and the Results show that HDL can deliver miRNAs to cells. The paper does not examine people with HDL below the fifth centile, establish that they have less circulating miRNA, or link miRNA amounts to adaptive impairment. (LLM, conf=0.78)
Experimental — accuracy not yet measuredReduced blood HDL levels reduce the number of particles available for the transport of miRNA.
“Since 90% of miRNA are carried by HDL and reduced blood HDL levels have been shown to reduce the number of particles available for the transport of miRNA [5]”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [5]
The Abstract (page unavailable) states that HDL transports miRNAs, and the Results section on reconstituted HDL (page unavailable) shows that HDL can acquire miRNAs in vivo. The paper does not show that reduced blood HDL levels reduce the number of particles available for miRNA transport. It also does not establish the citing sentence’s claim that HDL carries 90% of miRNA. (LLM, conf=0.86)
Experimental — accuracy not yet measured90% of miRNA are carried by HDL.
“Since 90% of miRNA are carried by HDL and reduced blood HDL levels have been shown to reduce the number of particles available for the transport of miRNA [5]”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [5]
The Discussion states that HDL transports endogenous miRNAs, but our copy does not say that HDL carries 90% of miRNAs. It also does not establish the citing sentence’s claim that reduced blood HDL levels reduce the number of particles available for miRNA transport. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmiR-21 co-localizes with GFP in EVs, but is also present in high-density fractions possibly associated with high-density lipoproteins.
“Overall, miR-21 was found to co-localize with GFP, but miR-21 was also present in the high-density fractions, possibly associated with high-density lipoproteins (Figures S2B and S2C) (Vickers et al., 2011).”
From Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21 (2019) · cites this paper as Vickers et al., 2011
Other proteins found to bind extracellular miRNAs include high-density lipoprotein and nucleophosmin 1.
“Other proteins found to bind extracellular miRNAs include high-density lipoprotein (HDL) (126, 127) and nucleophosmin 1 (NPM1) (110, 118, 128).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [126]
Vesicle-free miRNAs associated with HDL are taken up by HDL receptor and scavenger receptor BI (SR-BI) in the plasma membrane of target cells.
“Furthermore, vesicle-free miRNAs associated with HDL are taken up by HDL receptor and scavenger receptor BI (SR-BI) receptor in the plasma membrane of the target cells (126, 127).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [126]
Native HDL is involved in transportation of endogenous microRNAs and their delivery to recipient cells.
“Vickers et al.66 have demonstrated that native HDL is involved in more complex intracellular communications such as the transportation of endogenous microRNAs and their delivery to recipient cells.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [66]
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- Authors
- Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D., & Remaley, A. T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Vickers, Kasey C.
- Venue
- Nature Cell Biology
- Published
- 2011-03-20
- Volume
- 13
- Issue
- 4
- Pages
- 423-433
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3074610
- OpenAlex
- W2032696674
- Cited by
- 2,741
- References
- 63
- Citations by year
- 2026: 73 · 2025: 98 · 2024: 115 · 2023: 152 · 2022: 172 · 2021: 202 · 2020: 236 · 2019: 204 · 2018: 224 · 2017: 222 · 2016: 248 · 2015: 236 · 2014: 223 · 2013: 190 · 2012: 111
- FWCI
- 60.70
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-12-23)
- Open access
- green
- europepmc.org
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 HL999999)
- National Heart, Lung, and Blood Institute (ZIAHL006091)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- microRNA, high-density lipoprotein, neutral sphingomyelinase, scavenger receptor class B type I, intercellular communication, atherosclerosis, familial hypercholesterolemia, hepatocytes, gene expression regulation, disease biomarkers
- MeSH terms
- Animals, Apolipoproteins E, Biological Transport, Gene Expression Regulation, Humans, Hyperlipoproteinemia Type II, Lipoproteins, HDL, Receptors, LDL, Biomarkers, Mice, Knockout, CD36 Antigens, MicroRNAs, Atherosclerosis, Mice
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