MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo
Open accessAbstract
MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1 and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.
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Written from the paper’s full text.
TL;DR
Humanized miR-33b knock-in mice were generated by inserting human miR-33b into intron 16 of mouse Srebf1, and they show reduced ABCA1/ABCG1/SREBP-1 protein, impaired macrophage cholesterol efflux, and lower HDL-C. A single miR-33b copy reduced HDL-C by almost 35%, suggesting miR-33b may contribute to lower human HDL-C and may act in a feedback mechanism on its host gene SREBF1.
Key findings
- miR-33b KI mice were viable, fertile, and had no obvious abnormalities up to 8 weeks; miR-33b expression in KI+/− mice was almost half that in KI+/+ mice, and tissue expression pattern was similar to Srebf1.
- LXR agonist T0901317 increased Srebf1 and miR-33b in parallel in primary hepatocytes and in vivo; T0901317-treated mice had average liver weight 1.5-fold greater than controls.
- Protein levels of ABCA1, ABCG1, and SREBP-1 were reduced in miR-33b KI liver/macrophages, while CPT1a, AMPKα, PCK1, G6PC, and CREB were unchanged; SRC1 was up-regulated. Macrophages from miR-33b KI+/+ mice had lower apoA-I- and HDL-C-mediated cholesterol efflux.
- Serum HDL-C was significantly decreased in miR-33b KI+/− and KI+/+ mice versus WT; HDL-C was reduced by almost 35% even in heterozygotes, one copy was sufficient to reduce HDL-C and total cholesterol to KI+/+ levels, and the decrease mainly comprised very large-, large-, and medium-sized HDLs, with no changes in TG levels.
Methods
- miR-33b KI mice were generated by inserting the human pre-miR-33b sequence into intron 16 of mouse Srebf1 using BAC recombineering, a loxP-flanked neomycin cassette, C57BL/6 ES cells, blastocyst injection, and Cre-mediated cassette removal; targeting was confirmed by Southern blotting, PCR, and sequencing, and experiments used male C57BL/6 background mice with WT littermate controls.
- HepG2 cells and mouse primary hepatocytes were treated with the LXR agonist T0901317; 8-week-old male miR-33b KI+/+ mice received T0901317 at 25 mg/kg for 3 days; peritoneal macrophages were used for cholesterol efflux assays with 3H-cholesterol/acLDL and apoA-I or HDL.
- Protein and RNA analyses used Western blotting and qRT-PCR/TaqMan microRNA assays; serum lipids were measured biochemically and by HPLC lipoprotein profiling; statistics used mean ± s.e.m. with unpaired two-tailed Student’s t-tests or one-way ANOVA with Bonferroni post hoc test, with p < 0.05 considered significant.
Limitations
- Stated: the authors did not identify miR-33b-specific target genes; previously reported miR-33b target genes were not reduced in miR-33b KI liver, possibly due to non-conserved binding sites in mice or compensatory mechanisms; they note the need to assess conditions with strong Srebf1 expression, species/diet differences for TG effects, and possible unexpected side effects of long-term therapeutic miR-33 modulation.
- Evident from the text: experiments were largely limited to male C57BL/6 mice at 8 weeks of age, with no human in vivo validation and no atherosclerosis or clinical outcome endpoints reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
1 of 5 cited sources checked · 1 supported · 0 flagged
- Findingcitation
The numbers of miR-33b transcripts were greater than those of miR-33a transcripts.
“In any event, the numbers of miR-33b transcripts were greater than those of miR-33a transcripts, and this underscores the importance of miR-33b21.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Rayner, K. J. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478, 404–407 (2011). source
- Findingown data
The decreased HDL levels mainly comprised very large-, large-, and medium-sized HDLs (mature HDLs).
“Moreover, the decreased HDL levels mainly comprised very large-, large-, and medium-sized HDLs (mature HDLs) (Fig. 5c and Supplementary Table S1).”
Quote in the paperNot a substantial claim - Findingown data
CPT1a and AMPKα protein levels remained unchanged in the livers of miR-33b KI mice.
“However, the protein levels of some of the previously defined miR-33a target genes, such as CPT1a and AMPKα remained unchanged.”
Quote in the paperNot a substantial claim - Findingown data
The relative tissue expression pattern of miR-33b was similar to that of Srebf1.
“Relative tissue expression pattern of miR-33b was similar to that of Srebf1 (Supplementary Fig. S2e and S2f).”
Quote in the paperNot a substantial claim - Findingown data
Only one copy of miR-33b was sufficient to substantially reduce HDL-C and total cholesterol to the same levels as in miR-33b KI+/+ mice.
“These results show that only one copy of miR-33b was sufficient to substantially reduce HDL-C and total cholesterol to the same levels as those in the miR-33b KI+/+ mice.”
Quote in the paperSubstantial claim
- Findingown data
ABCA1 and SREBP-1 protein levels were lower in the livers of miR-33b KI mice.
“ABCA1 and SREBP-1 protein levels were lower in the livers of the miR-33b KI mice.”
Quote in the paperSubstantial claim - Findingown data
Srebf1 levels were similar among wild-type and miR-33b KI mice in liver and peritoneal macrophages.
“Srebf1 levels were similar among these mice (Supplementary Figure S2c and S3c).”
Quote in the paperSubstantial claim - Findingown data
miR-33b expression levels in miR-33b KI+/− mice were almost half of those in miR-33b KI+/+ mice.
“The expression levels of miR-33b in miR-33b KI+/− mice were almost half of those in miR-33b KI+/+ mice (Fig. 2f).”
Quote in the paperNot a substantial claim - Findingown data
ABCA1 and ABCG1 protein levels were lower in macrophages from miR-33b KI+/+ mice than from wild-type mice.
“ABCA1 and ABCG1 protein levels were lower in macrophages from the miR-33b KI+/+ mice than from the WT mice (Fig. 5a and Supplementary Figure S3e and S3f)”
Quote in the paperSubstantial claim - Findingown data
In vivo, T0901317 treatment significantly increased Srebf1 and miR-33b expression levels in the liver in parallel.
“Srebf1 and miR-33b expression levels in the liver were also significantly increased in parallel (Fig. 3c and d).”
Quote in the paperNot a substantial claim - Findingown data
Macrophages from miR-33b KI+/+ mice had lower apoA-I- and HDL-C-mediated cholesterol efflux than those from wild-type mice.
“macrophages from the miR-33b KI+/+ mice had lower apoA-I- and HDL-C-mediated cholesterol efflux than those from the WT mice (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
Serum HDL-C levels were significantly decreased in miR-33b KI+/− and miR-33b KI+/+ mice compared with wild-type mice.
“Serum HDL-C levels were significantly decreased in the miR-33b KI+/− and miR-33b KI+/+ mice compared with the WT mice (Table).”
Quote in the paperSubstantial claim - Findingown data
Previously reported miR-33b target genes were not reduced in the liver of miR-33b KI mice compared with control mice.
“Even previously reported miR-33b target genes were not reduced in the liver of miR-33b KI mice compared with that of control mice.”
Quote in the paperSubstantial claim - Findingown data
No significant change in protein levels of PCK1, G6PC, and CREB was observed in the liver of miR-33b KI mice compared with control mice.
“However, no significant change in protein level was observed in PCK1, G6PC, and CREB in the liver of miR-33b KI mice compared with that of control mice.”
Quote in the paperNot a substantial claim - Findingown data
There was no difference in miR-33a levels in macrophages between wild-type and miR-33b KI mice.
“Although there was no difference in miR-33a levels in macrophages (Supplementary Figure S3b)”
Quote in the paperNot a substantial claim - Findingown data
The authors successfully established miR-33b knock-in mice for the same intron as in humans.
“We successfully established miR-33b knock-in (KI) mice for the same intron as in humans.”
- Also stated in: § Abstract · plain
“We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
The authors have not yet succeeded in identifying miR-33b-specific target genes.
“We have not yet succeeded in identifying miR-33b-specific target genes.”
Quote in the paperNot a substantial claim - Findingown data
miR-33b has a significant inhibitory effect on SREBP-1.
“In contrast, we found a significant inhibitory effect of miR-33b on SREBP-1.”
Quote in the paperSubstantial claim - Interpretationown data
miR-33b was co-expressed with Srebf1 in the livers of T0901317-treated miR-33b KI mice.
“These results indicate that miR-33b was co-expressed with Srebf1 in the livers of the T0901317-treated miR-33b KI mice.”
Quote in the paperNot a substantial claim - Interpretationown data
miR-33b functions to control HDL-C levels.
“Our data demonstrated that miR-33b indeed functions to control HDL-C levels, which highlights the importance of targeting both miR-33 family members simultaneously.”
Quote in the paperSubstantial claim - Interpretationown data
Modulation of miR-33s is unlikely to have a strong effect on triglyceride 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.”
Quote in the paperSubstantial claim - Premiseown data
miR-33a and miR-33b differ by a 2-nucleotide mismatch after the seed sequence.
“However, there remains a 2-nucleotide mismatch after the seed sequence between miR-33a and miR-33b (Supplementary Fig. 1a)”
Quote in the paperSubstantial claim - Interpretationown data
miR-33b reduction explains one reason why human HDL-C levels are lower than those of mice.
“This explains one of the reasons why human HDL-C levels are lower than those of mice and indicates that it is important to considerably reduce miR-33b levels if pharmacological targeting of miR-33s is used to increase HDL-C levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Human HDL-C levels are lower than those of mice.
- Study design and conductown data
The miR-33b knock-in strategy did not alter Srebf1 intron 16 splicing.
“This miR-33b KI strategy did not alter Srebf1 intron 16 splicing, as confirmed by PCR (Fig. 2d) and sequencing (Fig. 2e).”
Quote in the paperSubstantial claim - Interpretationown data
The authors demonstrated the effect of miR-33b on HDL-C levels in vivo.
“In the present study, we demonstrated the effect of miR-33b on HDL-C levels in vivo.”
Quote in the paperSubstantial claim - Interpretationreasoning
miR-33b may be utilized for a feedback mechanism to regulate its host gene SREBF1.
“miR-33b may be utilized for a feedback mechanism to regulate its host gene SREBF1 because insulin induces hepatic SREBP-1c expression and promotes lipogenesis and hepatic TG synthesis (Supplementary Fig. S6).”
Quote in the paperNot a substantial claim
- May combine two claims. 8
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataHDL-C levels were reduced by almost 35% even in miR-33b KI+/− mice compared with wild-type mice without any changes in triglyceride levels.
“Finally, HDL-C levels were reduced by almost 35% even in the miR-33b KI+/− mice compared with the WT mice without any changes in triglyceride (TG) levels.”
- Also stated in: § Abstract · plain
“Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
May combine two claims.
Findingown dataSRC1 was up-regulated in miR-33b KI mice, opposite to the results of a previous report.
“SRC1 was up-regulated in miR-33bKI mice and it was opposite to the results of previous report14.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Ramirez, C. M. et al. MicroRNA 33 regulates glucose metabolism. Mol Cell Biol 33, 2891–2902 (2013). source
May combine two claims.
Findingown datamiR-33b KI+/+ mice were born with expected Mendelian ratios, were viable, fertile, and had no obvious abnormalities in size, shape, or structure up to 8 weeks of age.
“The miR-33b KI+/+ mice were born with the expected Mendelian ratios, were viable, fertile, and did not exhibit any obvious abnormalities in size, shape, or structure up to 8 weeks of age.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn primary hepatocytes from miR-33b KI+/+ mice, T0901317 significantly increased Srebf1 and miR-33b mRNA levels in parallel, with the Srebf1 increase faster than that of miR-33b.
“When primary hepatocytes from the miR-33b KI+/+ mice were stimulated with T0901317, Srebf1 and miR-33b mRNA levels were significantly increased in parallel, although this increase was faster for Serbf1 than for miR-33b (Fig. 3a and b).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown datamiR-33a levels were increased in proportion to miR-33b expression levels in the liver.
“miR-33a levels were increased in proportion of the expression levels of miR-33b in the liver (Supplementary Figure S2b).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNo 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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Horie, T. et al. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci U S A 107, 17321–17326 (2010). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationmiR-33a controls ABCA1 expression and reduces HDL-C levels.
“Recent reports, including ours, indicated that miR-33a controls ABCA1 expression and reduces HDL-C levels678”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [678]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiR-33a deficiency ameliorates atherosclerosis in mice.
“and that miR-33a deficiency ameliorates atherosclerosis in mice91011”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites 91011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim. May combine two claims.
PremisereasoningmiR-33a and miR-33b are identical in their seed sequences and are predicted to repress the same set of genes with similar specificities.
“miR-33a and miR-33b are identical in their seed sequences, and thus have been predicted to repress the same set of genes with similar specificities.”
Quote in the paperSubstantial claimMay combine two claims.
Premiseown dataPrimates, but not rodents, express miR-33b from an intron of SREBF1.
“Primates, but not rodents, express miR-33b from an intron of SREBF1.”
- Also stated in: § Abstract · plain
“However, in rodents, a part of miR-33b is lacking from a Srebf1 intron (Supplementary Fig. 1a)”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
The authors state this as an assumption.
Inhibiting both miR-33a and miR-33b will have a significant effect on HDL-C levels in clinical settings.
“We assume that inhibiting both miR-33a and miR-33b will have a significant effect on HDL-C levels in clinical settings.”
The authors state this as an assumption.
A miR located within an intron of a gene is expressed along with its host gene and exerts its specific function.
“It is assumed that a miR located within an intron of a gene is expressed along with its host gene and exerts its specific function12.”
The paper relies on this without support.
Human HDL-C levels are lower than those of mice.
“This explains one of the reasons why human HDL-C levels are lower than those of mice”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A previously described miR-33b knockin model was reported to have decreased expression of ABCA1 and other miR-33 target genes in primary hepatocytes.
“a previously described miR-33b knockin model was reported to have decreased expression of ABCA1 and other miR-33 target genes in primary hepatocytes (Horie et al., 2014).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Horie et al., 2014
The Results section on miR-33b KI target proteins (page unavailable) reports lower ABCA1 and SREBP-1 protein levels in the livers of knock-in mice. The separate Results section on primary hepatocytes reports increased Srebf1 and miR-33b after stimulation, not decreased ABCA1 or other target-gene expression in those cells. The claimed primary-hepatocyte finding is therefore not supported. (LLM, conf=0.89)
Experimental — accuracy not yet measuredmiR-33b knock-in mice have been generated by inserting the human miR-33b sequence into the same Srebf1 intron as found in humans.
“however, miR-33b knock-in mice have been generated by inserting the human miR-33b sequence into the same Srebf1 intron as found in humans 16) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [16]
In miR-33b knock-in mice, both miR-33a and miR-33b are expressed, reflecting the human condition.
“In these mice, both miR-33a and miR-33b are expressed, reflecting the human condition.”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [16]
In contrast to miR-33a knockout mice, miR-33b knock-in mice exhibit decreased ABCA1 expression in macrophages and the liver, leading to reduced cholesterol efflux capacity in macrophages and decreased serum HDL cholesterol levels.
“In contrast to miR-33a knockout mice, miR-33b knock-in mice exhibit a decreased ABCA1 expression in macrophages and the liver, leading to a reduced cholesterol efflux capacity in macrophages and decreased serum HDL cholesterol levels.”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [16]
Cites
Circular RNAs are a large class of animal RNAs with regulatory potency
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., et al. (2013) · Nature · doi:10.1038/nature11928 · Cited by 7,990 · see citing works
Molecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin
Aziz, J., Shezali, H., Radzi, Z., Yahya, N. A., Abu Kassim, N. H., Czernuszka, J., & Rahman, M. T. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000447017 · Cited by 7,323 · see citing works
Chapter 4 Preparation of Isolated Rat Liver Cells
Seglen, P. O. (1976) · Methods in cell biology · doi:10.1016/s0091-679x(08)61797-5 · Cited by 5,297 · see citing works
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,285 · see citing works
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092 · see citing works
MiR-33 Contributes to the Regulation of Cholesterol Homeostasis
Rayner, K. J., Suárez, Y., Dávalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., & Fernández-Hernando, C. (2010) · Science · doi:10.1126/science.1189862 · Cited by 1,260 · see citing works
Yokoyama, C., Wang, X., Briggs, M. R., Admon, A., Wu, J., Hua, X., Goldstein, J. L., & Brown, M. S. (1993) · Cell · doi:10.1016/s0092-8674(05)80095-9 · Cited by 968 · see citing works
MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis
Najafi-Shoushtari, S. H., Kristo, F., Li, Y., Shioda, T., Cohen, D. E., Gerszten, R. E., & Näär, A. M. (2010) · Science · doi:10.1126/science.1189123 · Cited by 957 · see citing works
Recombineering: a powerful new tool for mouse functional genomics
Copeland, N. G., Jenkins, N. A., & Court, D. L. (2001) · Nature Reviews Genetics · doi:10.1038/35093556 · Cited by 739 · see citing works
Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Rayner, K. J., Esau, C. C., Hussain, F. N., McDaniel, A. L., Marshall, S. M., van Gils, J. M., Ray, T. D., Sheedy, F. J., Goedeke, L., Liu, X., et al. (2011) · Nature · doi:10.1038/nature10486 · Cited by 706 · see citing works
Rayner, K. J., Sheedy, F. J., Esau, C. C., Hussain, F. N., Temel, R. E., Parathath, S., van Gils, J. M., Rayner, A. J., Chang, A. N., Suarez, Y., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57275 · Cited by 690 · see citing works
Regulation of Sterol Synthesis in Eukaryotes
Espenshade, P. J., & Hughes, A. L. (2007) · Annual Review of Genetics · doi:10.1146/annurev.genet.41.110306.130315 · Cited by 593 · see citing works
Timmins, J. M., Lee, J.-Y., Boudyguina, E., Kluckman, K. D., Brunham, L. R., Mulya, A., Gebre, A. K., Coutinho, J. M., Colvin, P. L., Smith, T. L., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23915 · Cited by 447 · see citing works
Horie, T., Ono, K., Horiguchi, M., Nishi, H., Nakamura, T., Nagao, K., Kinoshita, M., Kuwabara, Y., Marusawa, H., Iwanaga, Y., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008499107 · Cited by 384 · see citing works
Self-citationExpression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation*
Gerin, I., Clerbaux, L.-A., Haumont, O., Lanthier, N., Das, A. K., Burant, C. F., Leclercq, I. A., MacDougald, O. A., & Bommer, G. T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.152090 · Cited by 382 · see citing works
Osborne, T. F., & Espenshade, P. J. (2009) · Genes & Development · doi:10.1101/gad.1854309 · Cited by 264 · see citing works
DeBose‐Boyd, R. A., Ou, J., Goldstein, J. L., & Brown, M. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1477 · Cited by 246 · see citing works
HLF/HIF‐2α is a key factor in retinopathy of prematurity in association with erythropoietin
Morita, M., Ohneda, O., Yamashita, T., Takahashi, S., Suzuki, N., Nakajima, O., Kawauchi, S., Ema, M., Shibahara, S., Udono, T., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg117 · Cited by 230 · see citing works
MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
Horie, T., Nishino, T., Baba, O., Kuwabara, Y., Nakao, T., Nishiga, M., Usami, S., Izuhara, M., Sowa, N., Yahagi, N., et al. (2013) · Nature Communications · doi:10.1038/ncomms3883 · Cited by 230 · see citing works
Self-citationBasso, F., Freeman, L. A., Knapper, C. L., Remaley, A. T., Stonik, J. A., Neufeld, E. B., Tansey, T. R., Amar, M. J., Fruchart‐Najib, J., Duverger, N., et al. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m200414-jlr200 · Cited by 228 · see citing works
MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice
Horie, T., Baba, O., Kuwabara, Y., Chujo, Y., Watanabe, S., Kinoshita, M., Horiguchi, M., Nakamura, T., Chonabayashi, K., Hishizawa, M., et al. (2012) · Journal of the American Heart Association · doi:10.1161/jaha.112.003376 · Cited by 220 · see citing works
Self-citationHorie, T., Ono, K., Nishi, H., Nagao, K., Kinoshita, M., Watanabe, S., Kuwabara, Y., Nakashima, Y., Takanabe‐Mori, R., Nishi, E., et al. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq148 · Cited by 208 · see citing works
Self-citationSREBPs: physiology and pathophysiology of the SREBP family
Shimano, H. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06806.x · Cited by 202 · see citing works
Self-citationFibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase
Horiguchi, M., Inoue, T., Ohbayashi, T., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908268106 · Cited by 173 · see citing works
Self-citationMicroRNAs and cardiovascular diseases
Ono, K., Kuwabara, Y., & Han, J. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2011.08090.x · Cited by 169 · see citing works
Self-citationMicroRNA 33 Regulates Glucose Metabolism
Ramírez, C. M., Goedeke, L., Rotllan, N., Yoon, J.-H., Cirera-Salinas, D., Mattison, J. A., Suárez, Y., de Cabo, R., Gorospe, M., & Fernández-Hernando, C. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00016-13 · Cited by 154 · see citing works
Rottiers, V., Obad, S., Petri, A., McGarrah, R., Lindholm, M. W., Black, J. C., Sinha, S., Goody, R. J., Lawrence, M. S., deLemos, A. S., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006840 · Cited by 121 · see citing works
MicroRNA Modulation of Cholesterol Homeostasis
Fernández-Hernando, C., & Moore, K. J. (2011) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.111.226688 · Cited by 89 · see citing works
Zhang, Z., Yamashita, S., Hirano, K., Nakagawa-Toyama, Y., Matsuyama, A., Nishida, M., Sakai, N., Fukasawa, M., Arai, H., Miyagawa, J., et al. (2001) · Atherosclerosis · doi:10.1016/s0021-9150(01)00490-7 · Cited by 62 · see citing works
Usui, S., Kakuuchi, H., Okamoto, M., Mizukami, Y., & Okazaki, M. (2002) · Clinical Chemistry · doi:10.1093/clinchem/48.11.1946 · Cited by 42 · see citing works
Zhou, X., He, W. S., Huang, Z., Gotto, A. M., Hajjar, D. P., & Han, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706636200 · Cited by 35 · see citing works
MicroRNAs and Lipoprotein Metabolism
Horie, T., Baba, O., Kuwabara, Y., Yokode, M., Kita, T., Kimura, T., & Ono, K. (2014) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.20859 · Cited by 29 · see citing works
Self-citationSowa, N., Horie, T., Kuwabara, Y., Baba, O., Watanabe, S., Nishi, H., Kinoshita, M., Takanabe‐Mori, R., Wada, H., Shimatsu, A., et al. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24222 · Cited by 22 · see citing works
Self-citation
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1 of the 34 references couldn’t be matched to a known paper.
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SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology
Shimano, H., & Sato, R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.91 · Cited by 1,174 · see citing works
Self-citationMicroRNAs and lipid metabolism
Aryal, B. K., Singh, A. K., Rotllán, N., Price, N. D., & Fernandez-Hernando, C. F. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000420 · Cited by 203 · see citing works
Karunakaran, D., Thrush, A. B., Nguyen, M.-A., Richards, L., Geoffrion, M., Singaravelu, R., Ramphos, E., Shangari, P., Ouimet, M., Pezacki, J. P., et al. (2015) · Circulation Research · doi:10.1161/circresaha.117.305624 · Cited by 188 · see citing works
Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis
Price, N. L., Rotllan, N., Canfrán-Duque, A., Zhang, X., Pati, P., Arias, N., Moen, J., Mayr, M., Ford, D. A., Baldán, Á., et al. (2017) · Cell reports · doi:10.1016/j.celrep.2017.10.023 · Cited by 129 · see citing works
microRNAs in lipoprotein metabolism and cardiometabolic disorders
Rotllán, N., Price, N. L., Pati, P., Goedeke, L., & Fernandez-Hernando, C. F. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.01.025 · Cited by 111 · see citing works
Niesor, E. J., Schwartz, G. G., Perez, A., Stauffer, A., Durrwell, A., Suchánková, G., Benghozi, R., Abt, M., & Kallend, D. G. (2015) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-015-6570-0 · Cited by 69 · see citing works
Nishiga, M., Horie, T., Kuwabara, Y., Nagao, K., Baba, O., Nakao, T., Nishino, T., Hakuno, D., Nakashima, Y., Nishi, H., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.309528 · Cited by 71 · see citing works
Self-citationMicro-RNAs and High-Density Lipoprotein Metabolism
Canfrán‐Duque, A., Lin, C., Goedeke, L., Suárez, Y., & Fernandez-Hernando, C. F. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.307028 · Cited by 64 · see citing works
MicroRNA regulation of macrophages in human pathologies
Wei, Y., & Schober, A. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2254-6 · Cited by 63 · see citing works
SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation
Price, N., Holtrup, B., Kwei, S. L., Wabitsch, M., Rodeheffer, M. S., Bianchini, L., Suárez, Y., & Fernández-Hernando, C. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00745-15 · Cited by 54 · see citing works
Wang, H., Luo, J., Zhang, T., Tian, H., Ma, Y., Xu, H., Yao, D., & Loor, J. J. (2016) · RNA Biology · doi:10.1080/15476286.2016.1164365 · Cited by 57 · see citing works
Functions of microRNA-33a/b and microRNA therapeutics.
Ono, K. (2016) · Journal of Cardiology · doi:10.1016/j.jjcc.2015.10.017 · Cited by 52 · see citing works
Self-citationHaczeyni, F., Poekes, L., Wang, H., Mridha, A. R., Barn, V., Haigh, W. G., Ioannou, G. N., Yeh, M. M., Leclercq, I. A., Teoh, N., et al. (2016) · Obesity · doi:10.1002/oby.21701 · Cited by 46 · see citing works
MicroRNAs and Circular RNAs in Lipoprotein Metabolism
Fernández-Tussy, P., Ruz-Maldonado, I., & Fernández-Hernando, C. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00934-3 · Cited by 36 · see citing works
MicroRNA regulation of cholesterol metabolism
Citrin, K. M., Fernandez-Hernando, C. F., & Suárez, Y. (2021) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14566 · Cited by 44 · see citing works
Ortega, R., Liu, B., & Persaud, S. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310777 · Cited by 41 · see citing works
microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity
Horie, T., Nakao, T., Miyasaka, Y., Nishino, T., Matsumura, S., Nakazeki, F., Ide, Y., Kimura, M., Tsuji, S., Rodriguez, R. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21107-5 · Cited by 49 · see citing works
Self-citationMicroRNA-33a/b in lipid metabolism – novel “thrifty” models.
Ono, K., Horie, T., Nishino, T., Baba, O., Kuwabara, Y., Yokode, M., Kita, T., & Kimura, T. (2015) · Circulation Journal · doi:10.1253/circj.cj-14-1252 · Cited by 30 · see citing works
Self-citationGenomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis
Rozhkova, A., Dmitrieva, V., Nosova, E., Dergunov, A., Limborska, S., & Dergunova, L. (2021) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd8120170 · Cited by 25 · see citing works
miR‐33 in cardiometabolic diseases: lessons learned from novel animal models and approaches
Price, N. L., Goedeke, L., Suárez, Y., & Fernández‐Hernando, C. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202012606 · Cited by 36 · see citing works
Nishino, T., Horie, T., Baba, O., Sowa, N., Hanada, R., Kuwabara, Y., Nakao, T., Nishiga, M., Nishi, H., Nakashima, Y., et al. (2018) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.118.311409 · Cited by 33 · see citing works
Self-citationMicroRNAs and High-Density Lipoprotein Cholesterol Metabolism
Ono, K., Horie, T., Nishino, T., Baba, O., Kuwabara, Y., & Kimura, T. (2015) · International Heart Journal · doi:10.1536/ihj.15-019 · Cited by 23 · see citing works
Self-citationKoyama, S., Horie, T., Nishino, T., Baba, O., Sowa, N., Miyasaka, Y., Kuwabara, Y., Nakao, T., Nishiga, M., Nishi, H., et al. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.119.012609 · Cited by 23 · see citing works
Self-citationHinske, L. C., dos Santos, F. R. C., Ohara, D. T., Lucila Ohno-machado, A., Kreth, S., & Galante, P. A. F. (2017) · Database · doi:10.1093/database/bax053 · Cited by 19 · see citing works
Gai, Y., Li, Y., Xu, Z., & Chen, J. (2019) · Fitoterapia · doi:10.1016/j.fitote.2019.104393 · Cited by 19 · see citing works
miRNAs and High-Density Lipoprotein metabolism
Baldán, Á., & Vallim, T. Q. D. A. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.01.021 · Cited by 17 · see citing works
MicroRNAs and Nonalcoholic Steatohepatitis: A Review
Morishita, A., Oura, K., Tadokoro, T., Fujita, K., Tani, J., Kobara, H., Ono, M., Himoto, T., & Masaki, T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914482 · Cited by 19 · see citing works
MicroRNA in cardio-metabolic disorders
Su, X., Nie, M., Zhang, G., & Wang, B. (2021) · Clinica Chimica Acta · doi:10.1016/j.cca.2021.03.024 · Cited by 17 · see citing works
Functional non‐coding RNAs in vascular diseases
Ono, K., Horie, T., Baba, O., et al. (2020) · FEBS Journal · doi:10.1111/febs.15678 · Cited by 15 · see citing works
Self-citationZhang, J., Shi, J., Yuan, C., Liu, X., Du, G., Fan, R., & Zhang, B. (2021) · Bioengineering · doi:10.3390/bioengineering9010006 · Cited by 14 · see citing works
Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis
Miyagawa, S., Horie, T., Nishino, T., Koyama, S., Watanabe, T., Baba, O., Yamasaki, T., Sowa, N., Otani, C., Matsushita, K., et al. (2023) · Life Science Alliance · doi:10.26508/lsa.202301902 · Cited by 14 · see citing works
Self-citationYamasaki, T., Horie, T., Koyama, S., Nakao, T., Baba, O., Kimura, M., Sowa, N., Sakamoto, K., Yamazaki, K., Obika, S., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-16017-5 · Cited by 13 · see citing works
Self-citationYang, M., Ebert, C., Hayward, M. D., Liu, W., McDonough, V. M., & Nickels, J. T. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00058-20 · Cited by 10 · see citing works
Truths and Controversies Concerning the Role of miRNAs in Atherosclerosis and Lipid Metabolism
Baldán, Á., & Fernández-Hernando, C. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000358 · Cited by 10 · see citing works
Liu, S., Luo, T., Song, Y., et al. (2022) · Journal of Functional Foods · doi:10.1016/j.jff.2022.105347 · Cited by 8 · see citing works
Epigenetic factors in atherogenesis: microRNA
Smirnova, A. V., Sukhorukov, V. N., Карагодин, В. П., & Orekhov, A. N. (2016) · Biomeditsinskaya Khimiya · doi:10.18097/pbmc20166202134 · Cited by 7 · see citing works
Khalifeh, M., Santos, R. D., Oskuee, R. K., Badiee, A., Aghaee‐Bakhtiari, S. H., & Sahebkar, A. (2022) · Progress in Lipid Research · doi:10.1016/j.plipres.2022.101197 · Cited by 6 · see citing works
Human MicroRNA-33b Promotes Atherosclerosis in Apoe −/− Mice
Hussain, M. M., & Goldberg, I. J. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311617 · Cited by 6 · see citing works
Horie, T., Baba, O., Nishino, T., Yamashita, Y., Tsujisaka, Y., & Ono, K. (2026) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv22045 · Cited by 5 · see citing works
Self-citationMicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration
Sowa, N., Horie, T., Ide, Y., Baba, O., Kora, K., Yoshida, T., Nakamura, Y., Matsumura, S., Matsushita, K., Imanaka, M., et al. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00273-9 · Cited by 4 · see citing works
Self-citationMohammadi, S., Ebrahimi‐Mameghani, M., Arefhosseini, S. R., Fallah, P., Jafarabadi, M. A., Vahed, S. Z., Soleimani, M., Dehkordi, M. B., & Ghanbarian, H. (2016) · Iranian Red Crescent Medical Journal · doi:10.5812/ircmj.37521 · Cited by 3 · see citing works
MicroRNA-Linked Heart Disease and Therapeutic Potential
Ono, K. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-800553-8.00010-x · Cited by 3 · see citing works
Self-citationEkici, S., & Özmen, Ö. (2020) · Journal of Equine Veterinary Science · doi:10.1016/j.jevs.2020.103218 · Cited by 2 · see citing works
miR-33 inhibition as a novel therapeutic approach for treating muscular dystrophy
Lopez, M. A., & Alexander, M. S. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00271-x · Cited by 2 · see citing works
Noncoding RNAs in Cholesterol Metabolism and Atherosclerosis
Price, N., & Fernández-Hernando, C. (2017) · Cardiac and vascular biology · doi:10.1007/978-3-319-52945-5_2 · Cited by 1 · see citing works
Proregenerative MicroRNAs to Repair the Damaged Heart
Olianti, C., & Giacca, M. (2025) · European Cardiology Review · doi:10.15420/ecr.2025.34 · Cited by 1 · see citing works
尾野, 亘. (2015) · Journal of JCS Cardiologists · doi:10.1253/jjcsc.23.2_196
Koumaré, A. K., Compaore, T. R., Soudre, F. M., et al. (2019) · Advances in Biochemistry · doi:10.11648/j.ab.20190704.11
Epigenetic factors in atherogenesis: MicroRNA
Smirnova, A., Sukhorukov, V., Karagodin, V., & Orekhov, A. N. (2016) · Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry · doi:10.1134/s199075081603015x · Cited by 3 · see citing works
- Authors
- Horie, T., Nishino, T., Baba, O., Kuwabara, Y., Nakao, T., Nishiga, M., Usami, S., Izuhara, M., Nakazeki, F., Ide, Y., Koyama, S., Sowa, N., Yahagi, N., Shimano, H., Nakamura, T., Hasegawa, K., Kume, N., Yokode, M., Kita, T., Kimura, T., & Ono, K.
- Affiliations
- Kyoto University (JP)
- University of Tsukuba (JP)
- Kansai Medical University (JP)
- Kyoto Medical Center (JP)
- Kobe Gakuin University (JP)
- Kobe City Medical Center General Hospital (JP)
- ORCID
- Venue
- Scientific Reports
- Published
- 2014-06-16
- Volume
- 4
- Issue
- 1
- Pages
- 5312-5312
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4058878
- OpenAlex
- W2130907340
- Semantic Scholar
- 807313a2616ca5a2d14a342b21db5df9fc89bd18
- Cited by
- 49
- References
- 34
- Citations by year
- 2025: 4 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 13 · 2015: 6
- FWCI
- 7.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- Suzuken Memorial Foundation
- Cell Science Research Foundation
- Japan Foundation for Applied Enzymology
- Kowa Company
- Ministry of Education, Culture, Sports, Science and Technology
- Daiichi-Sankyo
- Kowa Life Science Foundation
- Otsuka Pharmaceutical
- Ono Medical Research Foundation
- SENSHIN Medical Research Foundation
- Japan Society for the Promotion of Science (23116006, 26461144, 26670147, 25461369)
- 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-33b, SREBF1, miR-33a, HDL cholesterol, cholesterol efflux, ABCA1, ABCG1, SREBP1, macrophages, apolipoprotein A-I, cholesterol homeostasis, atherosclerosis, humanized mice, host gene regulation
- MeSH terms
- Animals, Base Sequence, Cells, Cultured, Humans, Introns, Cholesterol, HDL, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Sequence Homology, Nucleic Acid, Blotting, Western, Macrophages, Peritoneal, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, MicroRNAs, Sterol Regulatory Element Binding Protein 1, Hep G2 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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