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MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis
Open accessAbstract
miR-33 in Cholesterol Control: With the well-established link between serum cholesterol levels and cardiovascular disease and the availability of effective cholesterol-lowering drugs, cholesterol screening has rapidly become a routine part of health care. Yet, much remains to be learned about how cholesterol levels are regulated at the cellular level (see the Perspective by Brown et al. ). Now, Najafi-Shoushtari et al. (p. 1566 , published online 13 May) and Rayner et al. (p. 1570 , published online 13 May) have discovered a new molecular player in cholesterol control—a small noncoding RNA that, intriguingly, is embedded within the genes coding for sterol regulatory element-binding proteins (SREBPs), transcription factors already known to regulate cholesterol levels. This microRNA, called miR-33, represses expression of the adenosine triphosphate–binding cassette transporter A1, a protein that regulates synthesis of high-density lipoprotein (HDL, or “good” cholesterol) and that helps to remove “bad” cholesterol from the blood. Reducing the levels of miR-33 in mice boosted serum HDL levels, suggesting that manipulation of this regulatory circuit might be therapeutically useful.
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“Pharmacological inhibition of miR-33 increased plasma high-density lipoprotein cholesterol levels in mice (Horie et al., 2010;Najafi-Shoushtari et al., 2010;Rayner et al., 2011a) and primates (Rayner et al., 2011b;Rottiers et al., 2013), leading to a marked reduction of atherosclerosis phenotypes.”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Najafi-Shoushtari et al., 2010
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In the citing paper
“in vivo antagonism or genetic deletion of miR-33 enhances hepatic ABCA1 expression and increases circulating HDL-cholesterol (HDL-C) (Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Najafi-Shoushtari et al., 2010
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These differences in miRNA expression vary between cell types suggesting that the role of miR-33b in the liver, where miR-33 is most highly expressed both in our mouse model and in human tissues (Najafi-Shoushtari et al., 2010), and other tissues may be considerably more important.”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Najafi-Shoushtari et al., 2010
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“In miR-33a knockout mice or when miR-33a is suppressed by synthetic nucleic acids such as antagomirs, the expression of ABCA1 in macrophages and the liver is increased 11 - 15) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [11]
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In the citing paper
“MicroRNA (miR)-33 is known to target ABCA1 and ABCG1 in vivo.”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE −/− Mice (2012) · cites this paper as [17]
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“Two miR-33 genes are present in humans: miR-33b, which is present in intron 17 of the Srebp-1 gene on chromosome 17, and miR-33a, which is located in intron 16 of the Srebp-2 gene on chromosome 22.”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We and others have recently established that, during sterol-limited states, miR-33a is coincidentally generated with Srebp-2 transcription and works to increase cellular cholesterol levels by limiting cholesterol export through the down-regulation of ABC transporters, ABCA1 and ABCG1 (12–14).”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [13]
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In the citing paper
“miR-33a and miR-33b are intronic miRNAs encoded within the SREBP-2 and SREBP-1 genes respectively (Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Najafi-Shoushtari et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“This work led to the demonstration that miR-33a and miR-33b are co-transcribed along with SREBP-2 and SREBP-1, and work in concert with their host genes to help maintain proper lipid levels within the cell (Davalos et al., 2011; Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Najafi-Shoushtari et al., 2010
The cited source says what the claim attributes to it.
In the citing paper
“The most well-known target gene of miR-33a/b is ATP-binding cassette subfamily A member 1 (ABCA1).”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Recent reports, including ours, have indicated that miR-33 controls cholesterol homeostasis based on knockdown experiments using antisense technology.16–18”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE −/− Mice (2012) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“We and others provided identification of a highly conserved miRNA family, miR-33, within the intronic sequences of the Srebp genes in organisms ranging from Drosophila to humans (11–14).”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“In mice, however, there is only one miR-33 gene, which is conserved with human miR-33a and located within intron 15 of the mouse Srebp-2 gene.”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Importantly, these pathways regulate circulating HDL levels through their roles in HDL biogenesis and cellular cholesterol efflux (12–14).”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [13]
In the citing paper
“These microRNAs participate in the regulation of cholesterol synthesis, fatty acid metabolism, and insulin signaling.”
From The Vasculature in Prediabetes (2018) · cites this paper as [143]
In the citing paper
“They are co-transcribed and act in conjunction with their host genes, Srebp1 and Srebp2, to regulate cholesterol synthesis.”
From The Vasculature in Prediabetes (2018) · cites this paper as [143]
In the citing paper
“Furthermore, an intronic microRNA located within Srebf2 gene, miR-33, inhibits the expression of Abca1 (Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
From Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP (2017) · cites this paper as Najafi-Shoushtari et al., 2010
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Metadata
- Authors
- Najafi-Shoushtari, S. H., Kristo, F., Li, Y., Shioda, T., Cohen, D. E., Gerszten, R. E., & Näär, A. M.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Näär, Anders M.
- ORCID
- Venue
- Science
- Published
- 2010-06-18
- Volume
- 328
- Issue
- 5985
- Pages
- 1566-1569
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3840500
- OpenAlex
- W2102901373
- Semantic Scholar
- 8e1f87e5a8c468d11cb938b52c20c8e6954402ce
- Cited by
- 957
- References
- 31
- Citations by year
- 2026: 20 · 2025: 30 · 2024: 24 · 2023: 47 · 2022: 41 · 2021: 56 · 2020: 50 · 2019: 65 · 2018: 66 · 2017: 59 · 2016: 86 · 2015: 88 · 2014: 85 · 2013: 92 · 2012: 73
- FWCI
- 80.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM071449)
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK084459, R01 DK48873, P30-DK34854, R01DK056626, R01 DK56626, R37DK048873, P30DK034854, R01DK048873)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- miR-33, cholesterol homeostasis, ABCA1, reverse cholesterol transport, HDL synthesis, cholesterol efflux, post-transcriptional regulation, antisense oligonucleotides, locked nucleic acid, cholesterol biosynthesis, cardiometabolic disease
- MeSH terms
- Animals, Cell Line, Cholesterol, Diet, Gene Expression Regulation, Homeostasis, Humans, Introns, Cholesterol, HDL, Liver, Macrophages, Mice, Inbred C57BL, Up-Regulation, Oligonucleotides, Antisense, ATP-Binding Cassette Transporters, 3' Untranslated Regions, RNA Interference, MicroRNAs, Mice, Sterol Regulatory Element Binding Proteins, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, ATP Binding Cassette Transporter 1
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