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Cited by 5MicroRNA in disease regulationCholesterol and Lipid MetabolismLipid metabolism and disorders

Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives

Open access
Horie, Takahiro, Baba, Osamu, Nishino, Tomohiro, Yamashita, Yugo, Tsujisaka, Yuta, Ono, Koh·2026·Journal of Atherosclerosis and Thrombosis
DOI 10.5551/jat.rv22045PMC PMC12782874
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Abstract

MicroRNAs (miRNAs) serve as fundamental post-transcriptional regulators of gene expression, among which the miR-33 family, consisting of miR-33a and miR-33b, has emerged as a critical modulator in the pathogenesis of cardiovascular and metabolic diseases. These miRNAs are embedded within the intronic regions of SREBF genes and play pivotal roles in cholesterol homeostasis, fatty acid metabolism, and inflammatory regulation. Notably, miR-33a is highly conserved across various species, whereas miR-33b is found primarily in primates and some other mammals, complicating the development of relevant animal models. These miRNAs inhibit their target genes involved in cholesterol metabolism, fatty acid oxidation, and insulin signaling, consequently influencing the development and progression of cardiovascular and metabolic diseases. Inhibition or genetic ablation of miR-33 has shown therapeutic potential, improving dyslipidemia, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease, through altered cholesterol metabolism, attenuation of inflammation, and increased fatty acid utilization. In addition, miR-33 suppression has been shown to promote skeletal muscle regeneration. However, systemic inhibition of miR-33 requires caution due to the role of miR-33 in hunger signaling and sympathetic nerve activity in the central nervous system, which may lead to obesity. Therefore, the development of tissue-specific strategies is essential for the safe and effective therapeutic targeting of miR-33.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how miR-33a and miR-33b, embedded in SREBF2 and SREBF1 introns, regulate cholesterol homeostasis, fatty acid oxidation, insulin signaling, inflammation, and skeletal muscle regeneration in cardiovascular and metabolic disease. It argues that miR-33 inhibition has therapeutic potential but requires tissue-specific strategies because systemic inhibition can alter central hunger signaling and sympathetic nerve activity, potentially promoting obesity.

Key findings

  • miR-33a resides in intron 16 of SREBF2 and is highly conserved across species including rodents; miR-33b resides in intron 17 of SREBF1 and is found primarily in primates and some other mammals but is absent in commonly used rodents such as mice and rats. The two isoforms differ by only two nucleotides but share the same seed sequences and largely shared target genes.
  • miR-33 targets genes involved in cholesterol metabolism and atherosclerosis (e.g., ABCA1, NPC1, OSBPL6, PRKAA1), fatty acid oxidation (e.g., CPT1A, HADHB, CROT, PRKAA1), insulin signaling and energy homeostasis (e.g., IRS2, SIRT6, PRKAA1, PPARGC1A), hunger signaling, GABA signaling, and skeletal muscle regeneration (e.g., CDK6, FST, ABCA1).
  • Inhibition or genetic ablation of miR-33 improves dyslipidemia, atherosclerosis, MASLD/MASH, and metabolic dysfunction in preclinical models; miR-33a knockout increases ABCA1 and HDL cholesterol, while miR-33b knock-in decreases ABCA1 and HDL cholesterol. miR-33 suppression also promotes skeletal muscle regeneration and ameliorates muscle damage in mdx mice.
  • Systemic miR-33a deletion can paradoxically cause obesity and insulin resistance on a high-fat diet via increased food intake and reduced sympathetic nerve activity/adaptive thermogenesis, while peripheral BAT inhibition enhances BAT activity, indicating that central versus peripheral balance is critical.

Methods

  • Narrative review of the biology, molecular mechanisms, and therapeutic perspectives of miR-33a/b in cardiovascular and metabolic disease, based on cited preclinical studies and prior literature.
  • Summarizes findings from genetically modified mouse models (miR-33a knockout, miR-33b knock-in, ApoE-deficient, LDL receptor-deficient, mdx), non-human primate studies, and in vitro/human cell approaches.
  • Includes a table of key features and representative target genes for miR-33a and miR-33b; no systematic search strategy, meta-analysis, or primary experimental data are reported.

Limitations

  • The paper states challenges for therapeutic translation: tissue specificity, isoform selectivity, long-term safety, and interspecies differences, particularly that miR-33b is present primarily in primates and some other mammals but absent in mice and rats.
  • The paper states that non-human primate studies have inherent limitations including small sample sizes, high costs, and ethical constraints, and should be integrated with complementary approaches such as human iPS cells, humanized rodent models, and ex vivo human tissues.
  • The paper states that systemic inhibition is problematic because central nervous system miR-33a deletion can lead to obesity, and that achieving effective delivery beyond the liver remains technically challenging; evident from the text, this is a narrative review without a systematic search or quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.5551/jat.rv22045

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

58 of 77 cited sources checked · 32 supported · 1 flagged · accuracy not yet measured

  • Interpretationcitation

    The obesity and insulin resistance in miR-33a knockout mice on a high-fat diet is attributed to a central nervous system phenotype, specifically an increase in food intake.

    “This has been attributed to a central nervous system phenotype, specifically an increase in food intake.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [39] 39) Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Sowa N, Yahagi N, Shimano H, Matsumura S, Inoue K, Marusawa H, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, and Ono K. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. Nat Commun, 2013; 4: 2883 source

      The Results section reports increased food intake in high-fat-diet-fed miR-33 knockout mice, but its pair-feeding experiment explicitly concludes that their greater weight gain is not caused by a change in food intake. The Discussion instead attributes obesity to enhanced SREBP-1 expression. The supplied passages have no page numbers. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [40] 40) Price NL, Singh AK, Rotllan N, Goedeke L, Wing A, Canfrán-Duque A, Diaz-Ruiz A, Araldi E, Baldán Á, Camporez JP, Suárez Y, Rodeheffer MS, Shulman GI, de Cabo R, and Fernández-Hernando C. Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Rep, 2018; 22: 2133-2145 source

      The Results report that increased food intake was primarily responsible for obesity and metabolic dysfunction in high-fat-diet-fed miR-33 knockout mice: pair feeding removed the differences in weight gain and metabolic regulation. The Discussion raises a direct effect on hypothalamic neurons only as a possibility, so the paper does not establish that the increased food intake is a central nervous system phenotype. Page numbers were not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Inhibition or genetic ablation of miR-33a promotes regression of atherosclerosis or prevents its formation in mouse models such as LDL receptor-deficient or ApoE-deficient mice, conferring resistance to the disease.

    “Inhibition or genetic ablation of miR-33a has been shown to either promote the regression of atherosclerosis or prevent its formation in mouse models, such as LDL receptor-deficient or apoprotein E (ApoE)-deficient mice, conferring resistance to the disease 21 - 23) .”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [21] 21) Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, and Moore KJ. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest, 2011; 121: 2921-2931 source
    • cites [22] 22) Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, Horiguchi M, Nakamura T, Chonabayashi K, Hishizawa M, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, and Ono K. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J Am Heart Assoc, 2012; 1: e003376 source

      The Introduction reports that antisense inhibition of miR-33 promoted plaque regression in LDL-receptor-deficient mice, and the Discussion reports smaller plaques in miR-33-deficient ApoE-deficient mice. But the paper describes the latter result as reduced progression of advanced atherosclerosis, not prevention of plaque formation or complete resistance to the disease. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [23] 23) Rotllan N, Ramírez CM, Aryal B, Esau CC, and Fernández-Hernando C. Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr-/- mice--brief report. Arterioscler Thromb Vasc Biol, 2013; 33: 1973-1977 source

      The Results report smaller atherosclerotic lesions after anti-miR-33 treatment in Ldlr−/− mice. The Discussion also reports plaque regression in a prior Ldlr−/− study and decreased atherosclerosis in miR-33−/− Apoe−/− mice. These passages support reduced disease and regression, but not the stronger claim that atherosclerosis formation was prevented or that the mice were resistant to the disease. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] 16) 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, and Ono K. MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo. Sci Rep, 2014; 4: 5312 source
  • Premisecitation

    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) .”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [11] 11) Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, and Näär AM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science, 2010; 328: 1566-1569 source

      The Results (page unavailable) report that anti-miR-33a/b oligonucleotides increased ABCA1 in cell lines including mouse macrophages and human liver carcinoma cells. In mice given miR-33a antisense, the paper reports only modest effects on hepatic ABCA1; it does not report results from miR-33a knockout mice. Thus, it supports the antisense finding but not the full claim as stated. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [12] 12) Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, and Fernández-Hernando C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science, 2010; 328: 1570-1573 source

      The supplied passages (labeled Abstract; page unavailable) report that anti-miR-33 increased ABCA1 expression in macrophages and hepatocytes, and that mice expressing anti-miR-33 had increased hepatic ABCA1 protein. They do not report results from miR-33a knockout mice; the knockout mice mentioned in the copy are Ldlr−/− and Apoe−/− mice. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [13] 13) Marquart TJ, Allen RM, Ory DS, and Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci U S A, 2010; 107: 12228-12232 source
    • cites [14] 14) 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, and Kita T. 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, 2010; 107: 17321-17326 source
    • cites [15] 15) Gerin I, Clerbaux LA, Haumont O, Lanthier N, Das AK, Burant CF, Leclercq IA, MacDougald OA, and Bommer GT. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem, 2010; 285: 33652-33661 source

      In “miR-33 in Cholesterol and Fatty Acid Metabolism” (p. 33655), the paper reports increased ABCA1 protein after miR-33 inhibition with sponges in HepG2 liver-derived cells; it also tests antagomirs in those cells. It does not report miR-33a knockout mice or show increased ABCA1 after suppression in mouse liver or macrophages. Its macrophage experiment instead tests miR-33a overexpression. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    miR-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) .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] 16) 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, and Ono K. MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo. Sci Rep, 2014; 4: 5312 source
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] 16) 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, and Ono K. MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo. Sci Rep, 2014; 4: 5312 source

  • May combine two claims.

    Premisecitation

    miR-33a and miR-33b differ by only two nucleotides and share the same seed sequences.

    “Although miR-33a and miR-33b differ by only two nucleotides, they share the same seed sequences, and their functions have been found to be relevant through comprehensive target analysis 10) .”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] 10) Koyama S, Horie T, Nishino T, Baba O, Sowa N, Miyasaka Y, Kuwabara Y, Nakao T, Nishiga M, Nishi H, Nakashima Y, Nakazeki F, Ide Y, Kimura M, Tsuji S, Ruiz Rodriguez R, Xu S, Yamasaki T, Otani C, Watanabe T, Nakamura T, Hasegawa K, Kimura T, and Ono K. Identification of Differential Roles of MicroRNA-33a and -33b During Atherosclerosis Progression With Genetically Modified Mice. J Am Heart Assoc, 2019; 8: e012609 source

  • May combine two claims.

    Premisecitation

    Macrophages within atherosclerotic lesions of these mice exhibit an anti-inflammatory phenotype characterized by enhanced cholesterol efflux, leading to a reduction in foam cell formation.

    “Furthermore, macrophages within the atherosclerotic lesions of these mice exhibit an anti-inflammatory phenotype characterized by enhanced cholesterol efflux, which leads to a reduction in foam cell formation.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [21] 21) Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, and Moore KJ. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest, 2011; 121: 2921-2931 source
    • cites [22] 22) Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, Horiguchi M, Nakamura T, Chonabayashi K, Hishizawa M, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, and Ono K. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J Am Heart Assoc, 2012; 1: e003376 source

      The Results section on peritoneal macrophages (page unavailable) reports enhanced cholesterol efflux in miR-33-deficient ApoE−/− mice, and the Discussion reports reduced plaque lipid content. But efflux was measured in peritoneal, not lesional, macrophages; the paper does not establish reduced foam-cell formation as its consequence. The Results and Discussion describe mixed pro- and anti-inflammatory markers rather than a straightforward anti-inflammatory macrophage phenotype. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] 23) Rotllan N, Ramírez CM, Aryal B, Esau CC, and Fernández-Hernando C. Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr-/- mice--brief report. Arterioscler Thromb Vasc Biol, 2013; 33: 1973-1977 source

      The Results (page not provided) report that HDL from anti-miR-33-treated mice increased macrophage cholesterol efflux and that treated plaques had fewer macrophages. The authors suggest this may mediate an anti-inflammatory effect in the artery wall, but they do not establish an anti-inflammatory phenotype in lesion macrophages or show that efflux reduced foam cell formation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Inhibition of miR-33a or miR-33a deletion in macrophages affects myeloid cell differentiation, induces M2 macrophage polarization with mitochondrial respiratory and metabolic changes, and enhances autophagy.

    “Inhibition of miR-33a or miR-33a deletion in macrophages has been shown to affect myeloid cell differentiation 25) , induce M2 macrophage polarization with mitochondrial respiratory and metabolic changes 26 , 27) , and enhance autophagy 28 , 29) .”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [25] 25) Baba O, Horie T, Nakao T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and Ono K. MicroRNA 33 Regulates the Population of Peripheral Inflammatory Ly6C. Mol Cell Biol, 2018; 38: e00604-17 source

      The Results section reports that miR-33-deficient mice had increased myeloid progenitors and attributes this to reduced apoptosis in hematopoietic stem cells. This supports the myeloid-cell portion attached to citation 25, but the study does not establish that miR-33a deletion specifically in macrophages causes that change. M2 polarization and autophagy are attached to other citations in the citing sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [26] 26) Ouimet M, Ediriweera HN, Gundra UM, Sheedy FJ, Ramkhelawon B, Hutchison SB, Rinehold K, van Solingen C, Fullerton MD, Cecchini K, Rayner KJ, Steinberg GR, Zamore PD, Fisher EA, Loke P, and Moore KJ. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest, 2015; 125: 4334-4348 source
    • cites [27] 27) Karunakaran D, Thrush AB, Nguyen MA, Richards L, Geoffrion M, Singaravelu R, Ramphos E, Shangari P, Ouimet M, Pezacki JP, Moore KJ, Perisic L, Maegdefessel L, Hedin U, Harper ME, and Rayner KJ. Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis. Circ Res, 2015; 117: 266-278 source

      The Results section ('Anti-miR33 treatment increases mitochondrial respiration and ATP production'; page not provided) reports increased respiration and ATP production after miR-33 inhibition in macrophages. The cited paper does not establish that this treatment induces M2 macrophage polarization. The sentence assigns myeloid differentiation and autophagy to other citations, so those claims are not judged here. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [28] 28) Ouimet M, Ediriweera H, Afonso MS, Ramkhelawon B, Singaravelu R, Liao X, Bandler RC, Rahman K, Fisher EA, Rayner KJ, Pezacki JP, Tabas I, and Moore KJ. microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis. Arterioscler Thromb Vasc Biol, 2017; 37: 1058-1067 source
    • cites [29] 29) Ahangari F, Price NL, Malik S, Chioccioli M, Bärnthaler T, Adams TS, Kim J, Pradeep SP, Ding S, Cosmos C, Rose KS, McDonough JE, Aurelien NR, Ibarra G, Omote N, Schupp JC, DeIuliis G, Villalba Nunez JA, Sharma L, Ryu C, Dela Cruz CS, Liu X, Prasse A, Rosas I, Bahal R, Fernández-Hernando C, and Kaminski N. microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis. JCI Insight, 2023; 8: e158100 source

  • May combine two claims.

    Premisecitation

    miR-33b knock-in exacerbates the formation of AAA, whereas inhibition of miR-33b with synthetic nucleic acids suppresses their progression.

    “It also exacerbates the formation of AAA, whereas the inhibition of miR-33b with synthetic nucleic acids suppresses their progression 33) .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] 33) Yamasaki T, Horie T, Koyama S, Nakao T, Baba O, Kimura M, Sowa N, Sakamoto K, Yamazaki K, Obika S, Kasahara Y, Kotera J, Oka K, Fujita R, Sasaki T, Takemiya A, Hasegawa K, Minatoya K, Kimura T, and Ono K. Inhibition of microRNA-33b specifically ameliorates abdominal aortic aneurysm formation via suppression of inflammatory pathways. Sci Rep, 2022; 12: 11984 source

  • May combine two claims.

    Premisecitation

    Single-cell analyses have confirmed anti-inflammatory and profibrotic effects in macrophages, which can contribute to atheroprotective effects and plaque stabilization.

    “Single-cell analyses have confirmed their anti-inflammatory and profibrotic effects in macrophages, which can contribute to atheroprotective effects and plaque stabilization 30 , 31) .”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [30] 30) Afonso MS, Sharma M, Schlegel M, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Rahman K, Giannarelli C, Li H, Brown EJ, Khodadadi-Jamayran A, Fisher EA, and Moore KJ. miR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques. Circ Res, 2021; 128: 1122-1138 source

      The Results and Discussion (pages unavailable) link single-cell analysis of anti-miR-33-treated mouse plaques to reduced inflammatory macrophage signatures, increased tissue-reparative macrophage markers, and atheroprotective effects. They do not establish a profibrotic effect or demonstrate plaque stabilization; the reported outcomes include increased efferocytosis and reduced necrotic area. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [31] 31) Zhang X, Rotllan N, Canfrán-Duque A, Sun J, Toczek J, Moshnikova A, Malik S, Price NL, Araldi E, Zhong W, Sadeghi MM, Andreev OA, Bahal R, Reshetnyak YK, Suárez Y, and Fernández-Hernando C. Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression. Circ Res, 2022; 131: 77-90 source

  • May combine two claims.

    Premisecitation

    miR-33a knockout mice show enhanced skeletal muscle regeneration, and when crossbred with Duchene muscular dystrophy model mice (mdx mice), they exhibit ameliorated muscle damage and increased exercise tolerance.

    “MiR-33a knockout mice show enhanced skeletal muscle regeneration, and when crossbred with Duchene muscular dystrophy model mice (mdx mice), they exhibit ameliorated muscle damage and increased exercise tolerance.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] 45) Sowa N, Horie T, Ide Y, Baba O, Kora K, Yoshida T, Nakamura Y, Matsumura S, Matsushita K, Imanaka M, Zou F, Kume E, Kojima H, Qian Q, Kimura K, Otsuka R, Hara N, Yamasaki T, Otani C, Tsujisaka Y, Takaya T, Nishimura C, Watanabe D, Hasegawa K, Kotera J, Oka K, Fujita R, Takemiya A, Sasaki T, Kasahara Y, Obika S, Kimura T, and Ono K. MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration. EMBO Mol Med, 2025; 17: 1902-1925 source

  • May combine two claims.

    Premisecitation

    miR-33a knockout in hepatocytes reduces steatosis with improved insulin sensitivity and glucose homeostasis and suppresses the subsequent progression to MASH and hepatocellular carcinoma (HCC) by reducing the lipid burden in the liver.

    “MiR-33a knockout in hepatocytes reduces steatosis with improved insulin sensitivity and glucose homeostasis and suppresses the subsequent progression to MASH and hepatocellular carcinoma (HCC) by reducing the lipid burden in the liver 36 , 37) .”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [36] 36) Price NL, Zhang X, Fernández-Tussy P, Singh AK, Burnap SA, Rotllan N, Goedeke L, Sun J, Canfrán-Duque A, Aryal B, Mayr M, Suárez Y, and Fernández-Hernando C. Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis. Proc Natl Acad Sci U S A, 2021; 118: e2006478118 source
    • cites [37] 37) Fernández-Tussy P, Cardelo MP, Zhang H, Sun J, Price NL, Boutagy NE, Goedeke L, Cadena-Sandoval M, Xirouchaki CE, Brown W, Yang X, Pastor-Rojo O, Haeusler RA, Bennett AM, Tiganis T, Suárez Y, and Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression. JCI Insight, 2024; 9: e168476 source

  • May combine two claims.

    Premisecitation

    Administration of synthetic nucleic acids to inhibit miR-33a/b promotes muscle regeneration, suppresses tissue fibrosis, and improves muscle function.

    “The administration of synthetic nucleic acids to inhibit miR-33a/b promotes muscle regeneration, suppresses tissue fibrosis, and improves the muscle function.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] 45) Sowa N, Horie T, Ide Y, Baba O, Kora K, Yoshida T, Nakamura Y, Matsumura S, Matsushita K, Imanaka M, Zou F, Kume E, Kojima H, Qian Q, Kimura K, Otsuka R, Hara N, Yamasaki T, Otani C, Tsujisaka Y, Takaya T, Nishimura C, Watanabe D, Hasegawa K, Kotera J, Oka K, Fujita R, Takemiya A, Sasaki T, Kasahara Y, Obika S, Kimura T, and Ono K. MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration. EMBO Mol Med, 2025; 17: 1902-1925 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miR-33a suppresses several gamma-aminobutyric acid (GABA)-related proteins, thereby regulating state-dependent memory.

    “In addition, miR-33a has been shown to suppress several gamma-aminobutyric acid (GABA)-related proteins, thereby regulating state-dependent memory 42) .”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] 42) Jovasevic V, Corcoran KA, Leaderbrand K, Yamawaki N, Guedea AL, Chen HJ, Shepherd GM, and Radulovic J. GABAergic mechanisms regulated by miR-33 encode state-dependent fear. Nat Neurosci, 2015; 18: 1265-1271 source

      The Results section reports that miR-33 overexpression reduced several GABA-related proteins and that miR-33 levels influenced the threshold for GABAA receptor–mediated state-dependent fear. Our copy calls the microRNA miR-33, however, and does not identify it specifically as miR-33a. (LLM, conf=0.80)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-33 contributes to hepatic lipid accumulation by repressing fatty acid oxidation genes and promoting lipogenesis.

    “MiR-33 contributes to hepatic lipid accumulation by repressing fatty acid oxidation genes and promoting lipogenesis.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [36] 36) Price NL, Zhang X, Fernández-Tussy P, Singh AK, Burnap SA, Rotllan N, Goedeke L, Sun J, Canfrán-Duque A, Aryal B, Mayr M, Suárez Y, and Fernández-Hernando C. Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis. Proc Natl Acad Sci U S A, 2021; 118: e2006478118 source
    • cites [37] 37) Fernández-Tussy P, Cardelo MP, Zhang H, Sun J, Price NL, Boutagy NE, Goedeke L, Cadena-Sandoval M, Xirouchaki CE, Brown W, Yang X, Pastor-Rojo O, Haeusler RA, Bennett AM, Tiganis T, Suárez Y, and Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression. JCI Insight, 2024; 9: e168476 source

  • May combine two claims.

    Premisecitation

    Hepatic deletion of miR-33a reduces liver lipid content by suppressing lipid synthesis and enhancing fatty acid oxidation, improves mitochondrial function, and alleviates oxidative stress through AMPKα and PGC1α activation, leading to reduced activation of the YAP/TAZ pathway.

    “Hepatic deletion of miR-33a reduces liver lipid content by suppressing lipid synthesis and enhancing fatty acid oxidation, improves the mitochondrial function, and alleviates oxidative stress through AMPKα and PGC1α activation, leading to reduced activation of the YAP/TAZ pathway.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [36] 36) Price NL, Zhang X, Fernández-Tussy P, Singh AK, Burnap SA, Rotllan N, Goedeke L, Sun J, Canfrán-Duque A, Aryal B, Mayr M, Suárez Y, and Fernández-Hernando C. Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis. Proc Natl Acad Sci U S A, 2021; 118: e2006478118 source
    • cites [37] 37) Fernández-Tussy P, Cardelo MP, Zhang H, Sun J, Price NL, Boutagy NE, Goedeke L, Cadena-Sandoval M, Xirouchaki CE, Brown W, Yang X, Pastor-Rojo O, Haeusler RA, Bennett AM, Tiganis T, Suárez Y, and Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression. JCI Insight, 2024; 9: e168476 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-33a/b is abundantly expressed in skeletal muscle tissues and is important for muscular regeneration.

    “Recently, miR-33a/b was found to be abundantly expressed in skeletal muscle tissues and to be important for muscular regeneration.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [45] 45) Sowa N, Horie T, Ide Y, Baba O, Kora K, Yoshida T, Nakamura Y, Matsumura S, Matsushita K, Imanaka M, Zou F, Kume E, Kojima H, Qian Q, Kimura K, Otsuka R, Hara N, Yamasaki T, Otani C, Tsujisaka Y, Takaya T, Nishimura C, Watanabe D, Hasegawa K, Kotera J, Oka K, Fujita R, Takemiya A, Sasaki T, Kasahara Y, Obika S, Kimura T, and Ono K. MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration. EMBO Mol Med, 2025; 17: 1902-1925 source
    • cites [46] 46) Lopez MA, and Alexander MS. miR-33 inhibition as a novel therapeutic approach for treating muscular dystrophy. EMBO Mol Med, 2025; 17: 1893-1895 source

      The Abstract reports miR-33a expression in skeletal muscle and describes evidence that miR-33a/b affects muscle regeneration in mouse models. It does not establish that both miR-33a and miR-33b are abundantly expressed in skeletal muscle; the expression comparison given is for miR-33a alone. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-33b promotes steatohepatitis through its effects on hepatocytes or hepatic stellate cells, and its inhibition by synthetic nucleic acids suppresses steatohepatitis formation by reducing cholesterol and fatty acid accumulation.

    “Furthermore, studies using miR-33b knock-in mice have reported that miR-33b promotes steatohepatitis through its effects on hepatocytes or hepatic stellate cells and that its inhibition by synthetic nucleic acids suppresses steatohepatitis formation by reducing cholesterol and fatty acid accumulation 38) .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] 38) Miyagawa S, Horie T, Nishino T, Koyama S, Watanabe T, Baba O, Yamasaki T, Sowa N, Otani C, Matsushita K, Kojima H, Kimura M, Nakashima Y, Obika S, Kasahara Y, Kotera J, Oka K, Fujita R, Sasaki T, Takemiya A, Hasegawa K, Kimura T, and Ono K. Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis. Life Sci Alliance, 2023; 6: e202301902 source

      The Discussion (page unavailable) reports that miR-33b in hepatocytes worsened NAFLD/NASH in knock-in mice and that hepatic stellate-cell miR-33b may also contribute. It also reports that anti-miR-33b oligonucleotides reduced liver free cholesterol and triglycerides and improved fibrosis. The paper does not establish that treatment reduced fatty acid accumulation specifically; that part substitutes fatty acids for the measured triglycerides. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-33b knock-in mice show exacerbated muscle damage and reduced exercise tolerance.

    “In contrast, miR-33b knock-in mice show exacerbated muscle damage and reduced exercise tolerance.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] 45) Sowa N, Horie T, Ide Y, Baba O, Kora K, Yoshida T, Nakamura Y, Matsumura S, Matsushita K, Imanaka M, Zou F, Kume E, Kojima H, Qian Q, Kimura K, Otsuka R, Hara N, Yamasaki T, Otani C, Tsujisaka Y, Takaya T, Nishimura C, Watanabe D, Hasegawa K, Kotera J, Oka K, Fujita R, Takemiya A, Sasaki T, Kasahara Y, Obika S, Kimura T, and Ono K. MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration. EMBO Mol Med, 2025; 17: 1902-1925 source

      The Results section reports greater fibrosis and elevated serum CK, along with reduced exercise capacity, in miR-33b-KI/mdx mice compared with WT/mdx mice. The claim omits the mdx background: the same section says miR-33b-KI mice without mdx showed no apparent changes in muscle histology. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-33a deficiency decreases sympathetic nervous activity through the activation of GABAergic inhibitory neurons, mediated by the enhanced expression of GABAA receptor subunits such as GABRB2 and GABRA4, which leads to reduced adaptive thermogenesis primarily in brown adipose tissue (BAT) and contributes to obesity.

    “MiR-33a deficiency decreases sympathetic nervous activity through the activation of GABAergic inhibitory neurons, mediated by the enhanced expression of GABAA receptor subunits, such as GABRB2 and GABRA4, which leads to reduced adaptive thermogenesis primarily in brown adipose tissue (BAT) and contributes to obesity 43) .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] 43) Horie T, Nakao T, Miyasaka Y, Nishino T, Matsumura S, Nakazeki F, Ide Y, Kimura M, Tsuji S, Rodriguez RR, Watanabe T, Yamasaki T, Xu S, Otani C, Miyagawa S, Matsushita K, Sowa N, Omori A, Tanaka J, Nishimura C, Nishiga M, Kuwabara Y, Baba O, Watanabe S, Nishi H, Nakashima Y, Picciotto MR, Inoue H, Watanabe D, Nakamura K, Sasaki T, Kimura T, and Ono K. microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity. Nat Commun, 2012; 12: 843 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-33a controls hunger signaling in hypothalamic AgRP neurons possibly through several miR-33 target genes such as PRKAA1, Ppargc1a, CPT1a and CROT; thus, loss of miR-33a leads to increased feeding, obesity, and metabolic dysfunction in mice.

    “MiR-33a has been shown to control hunger signaling in hypothalamic AgRP neurons possibly through several miR-33 target genes such as PRKAA1, Ppargc1a, CPT1a and CROT; thus, loss of miR-33a leads to increased feeding, obesity, and metabolic dysfunction in mice 41) .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [41] 41) Price NL, Fernández-Tussy P, Varela L, Cardelo MP, Shanabrough M, Aryal B, de Cabo R, Suárez Y, Horvath TL, and Fernández-Hernando C. microRNA-33 controls hunger signaling in hypothalamic AgRP neurons. Nat Commun, 2024; 15: 2131 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    Increased ABCA1 expression enhances the cholesterol efflux capacity of macrophages and elevates serum HDL cholesterol levels.

    “Consequently, this enhances the cholesterol efflux capacity of macrophages and elevates serum HDL cholesterol levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    miR-33a knockout in mice suppresses the formation of abdominal aortic aneurysm (AAA) by increasing serum HDL cholesterol and promoting an anti-inflammatory response in both macrophages and vascular smooth muscle cells.

    “MiR-33a knockout in mice has also been reported to suppress the formation of abdominal aortic aneurysm (AAA) by increasing serum HDL cholesterol and promoting an anti-inflammatory response in both macrophages and vascular smooth muscle cells 24) .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] 24) Nakao T, Horie T, Baba O, Nishiga M, Nishino T, Izuhara M, Kuwabara Y, Nishi H, Usami S, Nakazeki F, Ide Y, Koyama S, Kimura M, Sowa N, Ohno S, Aoki H, Hasegawa K, Sakamoto K, Minatoya K, Kimura T, and Ono K. Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways. Arterioscler Thromb Vasc Biol, 2017; 37: 2161-2170 source

  • May combine two claims.

    Premisecitation

    In ApoE-deficient mice, miR-33b knock-in promotes an inflammatory shift in macrophages by promoting foam cell formation, impairing reverse cholesterol transport through reduced HDL cholesterol levels, accelerating the progression of atherosclerosis, and increasing the formation of unstable plaques.

    “In ApoE-deficient mice, miR-33b knock-in promotes an inflammatory shift in macrophages by promoting foam cell formation, impairing reverse cholesterol transport through reduced HDL cholesterol levels, accelerating the progression of atherosclerosis, and notably increasing the formation of unstable plaques 32) .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] 32) Nishino T, Horie T, Baba O, Sowa N, Hanada R, Kuwabara Y, Nakao T, Nishiga M, Nishi H, Nakashima Y, Nakazeki F, Ide Y, Koyama S, Kimura M, Nagata M, Yoshida K, Takagi Y, Nakamura T, Hasegawa K, Miyamoto S, Kimura T, and Ono K. SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo. Arterioscler Thromb Vasc Biol, 2018; 38: 2460-2473 source

  • May combine two claims.

    Interpretationreasoning

    Inhibition of miR-33 in preclinical models considerably improves metabolic outcomes and ameliorates disease phenotypes, providing a strong rationale for its therapeutic development.

    “Inhibition of miR-33 in preclinical models considerably improves metabolic outcomes and ameliorates disease phenotypes, providing a strong rationale for its therapeutic development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    miR-33 inhibition is considered to enhance fatty acid utilization and have an impact on steatosis treatment.

    “Conversely, miR-33 inhibition is considered to enhance fatty acid utilization and have an impact on steatosis treatment, as discussed in the next section.”
    Quote in the paperSubstantial claim
22 of 22

  • The paper relies on this without support.

    The expression of miR-33 is closely associated with that of its host genes.

    “The expression of miR-33 is closely associated with that of its host genes.”

  • The paper relies on this without support.

    When SREBFs are trans-activated by metabolic stimuli, both the host gene and the embedded miR-33 are co-transcribed.

    “When SREBFs are trans-activated by metabolic stimuli, such as low intracellular cholesterol (for SREBF2), insulin, or high carbohydrate intake (for SREBF1), both the host gene and the embedded miR-33 are co-transcribed.”

  • The paper relies on this without support.

    Skeletal muscle is a key organ in systemic metabolism and can influence whole-body metabolic homeostasis.

    “The skeletal muscle is a key organ in systemic metabolism and can therefore influence whole-body metabolic homeostasis.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Nature Communications reference volumes conflict with publication years

    Minor

    Reference 43 lists volume 12 as published in 2012, while reference 39 lists the earlier volume 4 as published in 2013. The volume-year information cannot both be correct for the same journal.

1 of 1

Cites

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Authors
Horie, T., Baba, O., Nishino, T., Yamashita, Y., Tsujisaka, Y., & Ono, K.
Affiliations
Kyoto University (JP)
ORCID
Venue
Journal of Atherosclerosis and Thrombosis
Publisher
Japan Atherosclerosis Society
Published
2026-01-01
Volume
33
Issue
1
Pages
13-19
ISSN
  • 1340-3478 (ISSN-L)
  • 1880-3873
DOI
10.5551/jat.rv22045
PMC
PMC12782874
OpenAlex
W4415529850
Cited by
5
References
46
Citations by year
2026: 5
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • Journal of Atherosclerosis and Thrombosis (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-sa)
  • Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by-nc-sa)
Funders
  • Japan Agency for Medical Research and Development (24ek0210202h0001)
  • Ministry of Education, Culture, Sports, Science and Technology
  • Japan Society for the Promotion of Science (17K09860, 20K08904, 23K07988)
  • Japan Science and Technology Agency
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
miR-33a, miR-33b, microRNA, cholesterol homeostasis, fatty acid metabolism, insulin signaling, inflammation, atherosclerosis, dyslipidemia, non-alcoholic fatty liver disease, skeletal muscle regeneration, obesity, cardiovascular disease, metabolic disorders
MeSH terms
Animals, Cardiovascular Diseases, Humans, Metabolic Diseases, MicroRNAs

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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.

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