MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 ( Srebp2 ) regulates HDL in vivo
Open accessAbstract
Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo.
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miR-33 negatively regulates ABCA1 in both the periphery and the brain.
“Previously, it was shown that miR‐33 negatively regulates ABCA1 in both the periphery and the brain. 15 , 16 , 17 , 18”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [15]
Mir-33 is encoded by intron 16 of the Srebf2 gene and is coexpressed with Srebf2.
“Mir‐33, which is encoded by intron 16 of the Srebf2 gene, is coexpressed with Srebf2. 15”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [15]
Pharmacological inhibition of miR-33 increased plasma HDL cholesterol levels in mice and primates, leading to a marked reduction of atherosclerosis phenotypes.
“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 Horie et al., 2010
ABCA1 expression is regulated by miR-33 in the periphery.
“Previously, we demonstrated that ABCA1 expression is regulated by miR-33 in the periphery (Horie et al., 2010;Rayner et al., 2010Rayner et al., , 2011a,b),b).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Horie et al., 2010
The most well-known target gene of miR-33a/b is ABCA1.
“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 [14]
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.
“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 [14]
No changes in triglyceride levels were observed in the present miR-33b KI study and in previous miR-33a KO experiments.
“In our present miR-33b KI study and in previous miR-33a KO experiments8, we did not observe any changes in TG levels, indicating that modulation of miR-33s is unlikely to have a strong effect on TG levels, although species differences and different dietary conditions need to be considered.”
From MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo (2014) · cites this paper as [8]
MicroRNA-33 targets ABCA1 and ABCG1 in vivo.
“MicroRNA (miR)-33 is known to target ABCA1 and ABCG1 in vivo.”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice (2012) · cites this paper as [22]
miR-33−/− mice show 22% to 39% higher serum HDL-C levels than wild-type mice.
“We previously reported that miR-33−/− mice showed 22% to 39% higher serum HDL-C levels than wild-type mice.22”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice (2012) · cites this paper as [22]
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Self-citation
- Authors
- Horie, T., Ono, K., Horiguchi, M., Nishi, H., Nakamura, T., Nagao, K., Kinoshita, M., Kuwabara, Y., Marusawa, H., Iwanaga, Y., Hasegawa, K., Yokode, M., Kimura, T., & Kita, T.
- Affiliations
- Kyoto University (JP)
- Kansai Medical University (JP)
- Kindai University (JP)
- Kyoto Medical Center (JP)
- Kobe City Medical Center General Hospital (JP)
- Corresponding author
- Ono, Koh
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-09-20
- Volume
- 107
- Issue
- 40
- Pages
- 17321-17326
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2951399
- OpenAlex
- W2154236306
- Cited by
- 384
- References
- 1
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 5 · 2023: 20 · 2022: 16 · 2021: 29 · 2020: 17 · 2019: 18 · 2018: 24 · 2017: 24 · 2016: 39 · 2015: 30 · 2014: 30 · 2013: 50 · 2012: 29
- FWCI
- 38.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science
- Institute of Molecular and Cell Biology
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- miR-33, HDL cholesterol, ABCA1, cholesterol efflux, apolipoprotein A-I, peritoneal macrophages, liver, cholesterol metabolism, HDL biogenesis
- MeSH terms
- Animals, Base Sequence, Cattle, Cell Line, Chickens, Female, Humans, Introns, Cholesterol, HDL, Macrophages, Molecular Sequence Data, Sequence Alignment, ATP-Binding Cassette Transporters, MicroRNAs, Mice, Sterol Regulatory Element Binding Protein 2, ATP Binding Cassette Transporter 1
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