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Cited by 670MicroRNA in disease regulationCholesterol and Lipid MetabolismLipid metabolism and disorders

miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling

Open access
Dávalos, Alberto, Goedeke, Leigh, Smibert, Peter, Ramírez, Cristina M., Warrier, Nikhil P., Andreo, Ursula, Cirera-Salinas, Daniel, Rayner, Katey +9 more·2011·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1102281108PMC PMC3107310
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Abstract

Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O -octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.

AI snapshot

Written from the paper’s full text.

TL;DR

miR-33a and miR-33b, intronic miRNAs of SREBP-2 and SREBP-1, directly target genes involved in fatty acid oxidation and insulin signaling, including CROT, CPT1a, HADHB, AMPKα, SIRT6, and IRS2. Overexpression reduces fatty acid oxidation and insulin signaling in hepatic cells, whereas inhibition increases them, suggesting miR-33 antagonism as a possible therapeutic strategy for metabolic syndrome.

Key findings

  • miR-33b repressed luciferase reporters containing the 3′ UTRs of Crot, Cpt1a, Hadhb, Ampkα, Irs2, and Sirt6; mutation of miR-33 target sites relieved repression. In Huh7 cells, miR-33b transfection (32-fold increase) inhibited CROT, CPT1a, HADHB, AMPKα, and IRS2 mRNA, while anti-miR-33b (threefold decrease) increased CROT, CPT1a, AMPKα, and IRS2 mRNA.
  • miR-33b overexpression (27-fold increase) reduced [14C]-oleate oxidation in Huh7 cells; anti-miR-33 (2.6-fold increase) increased fatty acid β-oxidation. miR-33b–transfected cells accumulated more triglycerides in larger lipid droplets without changes in basal or insulin-induced triglyceride synthesis. Drosophila fat body miR-33 overexpression caused large lipid droplets and increased TAG upon starvation.
  • miR-33b reduced insulin-stimulated AKT and ERK phosphorylation, in vitro AKT kinase activation, and 2-deoxyglucose uptake; IRS2 cDNA lacking the 3′ UTR rescued AKT activation and FoxO1 cytoplasmic translocation. miR-33a and -b differ by 2 nt of 19 nt of the mature RNA but showed similar targeting effects.
  • In mice, lentiviral miR-33 reduced hepatic CROT, HADHB, CPT1a, IRS2, and ABCA1 mRNA; anti-miR-33 produced modest increases in CROT, CPT1a, IRS2, and ABCA1 that were not statistically significant.

Methods

  • Cell-based assays in Huh7 and HepG2 hepatic cells: luciferase reporter constructs containing wild-type or mutated 3′ UTRs of predicted targets; transfection with miR-33a, miR-33b, anti-miR-33, or controls; mRNA/protein expression and 84-gene arrays for fatty acid and insulin-related genes.
  • Metabolic and signaling assays: fatty acid β-oxidation measured by release of [14C]-CO2 from [14C]-oleate; Bodipy staining and triglyceride measurement; insulin-stimulated AKT/ERK phosphorylation, AKT kinase assay, 2-deoxyglucose uptake, and FoxO1-GFP localization.
  • In vivo models: mouse lentiviral delivery of premiR-33, anti-miR-33, or control; Drosophila transgenic fat body overexpression of miR-33 with starvation, Bodipy staining, and TAG measurement. Detailed procedures are in SI Materials and Methods.

Limitations

  • The paper states that additional experiments, including RIPseq and proteomics, are warranted to understand the miR-33 regulatory network and its implications in lipid and carbohydrate metabolism.
  • The paper states that the functional relevance of the miR-33b/SREBP-1 association cannot easily be determined using traditional models of insulin resistance such as rats or mice, because their Srebp1 genes lack miR-33b; it also states that additional research and specialty clinical trials are needed to translate these therapies into clinical practice.
  • Evident from the text: much of the mechanistic evidence comes from hepatic cell lines and Drosophila, and the in vivo mouse anti-miR-33 effects on CROT, CPT1a, IRS2, and ABCA1 were modest and not statistically significant.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.1102281108

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

31 of 69 cited sources checked · 17 supported · 0 flagged · accuracy not yet measured

  • Findingown data
    § Results

    Bioinformatic analysis identified SIRT6 as a third miR-33 predicted target involved in glucose homeostasis.

    “In addition to IRS2 and FRS2, our bioinformatic analysis identified a third miR-33 predicted target involved in glucose homeostasis: the histone deacetylase SIRT6 (25, 26).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [25] Xiao C, et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J Biol Chem. 2010;285:36776–36784. doi: 10.1074/jbc.M110.168039. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [26] Zhong L, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140:280–293. doi: 10.1016/j.cell.2009.12.041. [DOI] [PMC free article] [PubMed] [Google Scholar] source
  • Premisecitation
    § Discussion

    Inhibition of miR-33a and -b effectively increases HDL in mice.

    “Although our previous work in mice supports this contention by showing that inhibition of miR-33a and -b effectively increases HDL (14)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The passage on the mouse experiment (indexed under Abstract; page unavailable) reports that anti-miR-33 increased plasma HDL by 25% after six days. The paper identifies the studied mouse miR-33 as the homolog of human miR-33a; our copy does not show that inhibition of miR-33b was tested in mice. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Discussion

    These pathways regulate circulating HDL levels through their roles in HDL biogenesis and cellular cholesterol efflux.

    “Importantly, these pathways regulate circulating HDL levels through their roles in HDL biogenesis and cellular cholesterol efflux (12–14).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [12] Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107:12228–12232. doi: 10.1073/pnas.1005191107. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [13] Najafi-Shoushtari SH, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–1569. doi: 10.1126/science.1189123. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source
  • Findingown data
    § Abstract

    miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including CROT, CPT1A, HADHB, SIRT6, and AMPKα.

    “miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α.”
    Quote in the paperSubstantial claim
  • Findingcitation
    § Results

    Several genes involved in fatty acid β-oxidation have predicted targets for miR-33, including CROT, CPT1a, HADHB, and AMPKα.

    “As shown in Fig. S2 (red box), several genes involved in fatty acid β-oxidation have predicted targets for miR-33, including CROT, CPT1a, HADHB and AMPKα (17–20).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Brady PS, Ramsay RR, Brady LJ. Regulation of the long-chain carnitine acyltransferases. FASEB J. 1993;7:1039–1044. doi: 10.1096/fasebj.7.11.8370473. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [18] Eaton S, et al. The mitochondrial trifunctional protein: Centre of a beta-oxidation metabolon? Biochem Soc Trans. 2000;28:177–182. doi: 10.1042/bst0280177. [DOI] [PubMed] [Google Scholar] source
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    • cites [20] Ramsay RR, Gandour RD. Selective modulation of carnitine long-chain acyltransferase activities. Kinetics, inhibitors, and active sites of COT and CPT-II. Adv Exp Med Biol. 1999;466:103–109. [PubMed] [Google Scholar]

      Not checked in the free run.

  • Classified as probably not a substantial claim. 23
  • May combine two claims. 20

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

    Premisecitation
    § Abstract

    miRNAs are critical regulators of gene expression acting predominantly at the posttranscriptional level.

    “a class of noncoding RNAs, termed microRNAs (miRNAs), has emerged as critical regulators of gene expression acting predominantly at the posttranscriptional level (8–10).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–355. doi: 10.1038/nature02871. [DOI] [PubMed] [Google Scholar] source
    • cites [9] Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell. 2009;136:215–233. doi: 10.1016/j.cell.2009.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [10] Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 2008;9:102–114. doi: 10.1038/nrg2290. [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Abstract

    In mice, there is only one miR-33 gene, conserved with human miR-33a and located within intron 15 of the mouse Srebp-2 gene.

    “In mice, however, there is only one miR-33 gene, which is conserved with human miR-33a and located within intron 15 of the mouse Srebp-2 gene.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [11] Gerin I, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem. 2010;285:33652–33661. doi: 10.1074/jbc.M110.152090. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The section “miR-33a Is Produced from an Intron of the SREBP2 Gene” says that mice possess miR-33a in SREBP2 but lack miR-33b, and describes miR-33a as highly conserved. It does not specify that the mouse sequence is in intron 15, so that part of the claim is unsupported by our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [12] Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107:12228–12232. doi: 10.1073/pnas.1005191107. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [13] Najafi-Shoushtari SH, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–1569. doi: 10.1126/science.1189123. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The sequence-alignment passage (indexed under Abstract; page unavailable) identifies mouse mmu-miR-33 as the homolog of human miR-33a and places it in SREBF2. It specifies intron 16, not intron 15, and does not establish that mice have only one miR-33 gene. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Abstract

    SREBP-1c regulates the transcription of genes involved in fatty acid metabolism, such as FASN.

    “SREBP-1c regulates the transcription of genes involved in fatty acid metabolism, such as fatty acid synthase (FASN) (5–7).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [5] Brown MS, Goldstein JL. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–340. doi: 10.1016/s0092-8674(00)80213-5. [DOI] [PubMed] [Google Scholar] source
    • cites [6] Horton JD, Goldstein JL, Brown MS. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–1131. doi: 10.1172/JCI15593. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [7] Osborne TF. Sterol regulatory element-binding proteins (SREBPs): Key regulators of nutritional homeostasis and insulin action. J Biol Chem. 2000;275:32379–32382. doi: 10.1074/jbc.R000017200. [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Abstract

    SREBP-2 regulates the transcription of cholesterol-related genes, such as HMGCR and LDLr.

    “SREBP-2 regulates the transcription of cholesterol-related genes, such as 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), which catalyzes a rate-limiting step in cholesterol biosynthesis, and the low-density lipoprotein receptor (LDLr), which imports cholesterol from the blood (5–7).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [5] Brown MS, Goldstein JL. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–340. doi: 10.1016/s0092-8674(00)80213-5. [DOI] [PubMed] [Google Scholar] source
    • cites [6] Horton JD, Goldstein JL, Brown MS. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–1131. doi: 10.1172/JCI15593. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [7] Osborne TF. Sterol regulatory element-binding proteins (SREBPs): Key regulators of nutritional homeostasis and insulin action. J Biol Chem. 2000;275:32379–32382. doi: 10.1074/jbc.R000017200. [DOI] [PubMed] [Google Scholar] source

      The section “Selective Roles for Individual SREBP Isoforms in Either Cholesterol or Fatty Acid Metabolism” says SREBP-2 may preferentially activate genes involved in cholesterol homeostasis, supporting the general point. The passages do not identify HMGCR or LDLr as SREBP-2 transcriptional targets; the specific LDL-receptor expression example instead concerns SREBP-1a. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Abstract

    miR-33 is a highly conserved miRNA family within the intronic sequences of the Srebp genes in organisms ranging from Drosophila to humans.

    “We and others provided identification of a highly conserved miRNA family, miR-33, within the intronic sequences of the Srebp genes in organisms ranging from Drosophila to humans (11–14).”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [11] Gerin I, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem. 2010;285:33652–33661. doi: 10.1074/jbc.M110.152090. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [12] Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107:12228–12232. doi: 10.1073/pnas.1005191107. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [13] Najafi-Shoushtari SH, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–1569. doi: 10.1126/science.1189123. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The passage on sequence alignment (section labeled Abstract; page unavailable) identifies human and mouse miR-33 within an intron of SREBF2 and says its precursor is highly conserved in mammals. Our copy does not establish a miR-33 family within Srebp genes across organisms ranging from Drosophila to humans. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Abstract

    miRNA targeting of mRNAs inhibits their expression through mRNA destabilization, repression of translation, or a combination of both processes.

    “miRNA targeting of mRNAs inhibits their expression through mRNA destabilization, repression of translation, or a combination of both processes (8–10).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–355. doi: 10.1038/nature02871. [DOI] [PubMed] [Google Scholar] source
    • cites [9] Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell. 2009;136:215–233. doi: 10.1016/j.cell.2009.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [10] Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 2008;9:102–114. doi: 10.1038/nrg2290. [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § Abstract

    miR-33a is cotranscribed with its host gene Srebp-2 and targets genes involved in cholesterol export, including ABCA1, ABCG1, and NPC1.

    “We recently showed that miR-33a is cotranscribed with its host gene Srebp-2 like many intronic miRNAs, and it targets genes involved in cholesterol export, including the adenosine triphosphate binding cassette (ABC) transporters ABCA1 and ABCG1 and the endolysosomal transport protein Niemann-Pick C1 (NPC1) (14).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The copy identifies hsa-miR-33a within an intron of SREBF2 and describes coincident transcription of SREBF2 and miR-33 (passages 8 and 7, labeled Abstract). It supports ABCA1 and NPC1 as targets, but explicitly limits ABCG1 targeting to mice; the unqualified claim that miR-33a targets ABCG1 omits that species restriction (passages 3–4, labeled Abstract). (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Abstract

    Two miR-33 genes are present in humans: miR-33b in intron 17 of Srebp-1 on chromosome 17, and miR-33a in intron 16 of Srebp-2 on chromosome 22.

    “Two miR-33 genes are present in humans: miR-33b, which is present in intron 17 of the Srebp-1 gene on chromosome 17, and miR-33a, which is located in intron 16 of the Srebp-2 gene on chromosome 22.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [11] Gerin I, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem. 2010;285:33652–33661. doi: 10.1074/jbc.M110.152090. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The section “miR-33a Is Produced from an Intron of the SREBP2 Gene” states that human miR-33a and miR-33b lie in introns of SREBP2 and SREBP1, respectively. Our copy does not give the claimed intron numbers or chromosome numbers, so those details are not supported by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [12] Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107:12228–12232. doi: 10.1073/pnas.1005191107. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [13] Najafi-Shoushtari SH, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–1569. doi: 10.1126/science.1189123. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results identify two human miR-33 isoforms and place miR-33b in intron 17 of SREBP-1 on chromosome 17. They place miR-33a in intron 15 of SREBP-2 on chromosome 22, not intron 16 as the citing sentence states. (LLM, conf=0.95)

      Experimental — accuracy not yet measured
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The passage labeled Abstract (page not supplied) identifies human miR-33a within intron 16 of SREBF2. Our copy does not state the chromosome 22 location or identify miR-33b in SREBF1 on chromosome 17, so it supports only part of the attributed sentence. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Results

    SIRT6-deficient mice develop normally but succumb to lethal hypoglycemia early in life, suggesting an important role of SIRT6 in regulating glucose metabolism.

    “SIRT6-deficient mice develop normally but succumb to lethal hypoglycemia early in life, suggesting an important role of SIRT6 in regulating glucose metabolism (25, 26).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [25] Xiao C, et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J Biol Chem. 2010;285:36776–36784. doi: 10.1074/jbc.M110.168039. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results section reports that SIRT6-deficient mice were born without obvious defects, but weighed less from postnatal day 3 and developed other abnormalities; it does not support saying they developed normally. The Abstract and Results support early hypoglycemia-related deaths in many mutants and a role for SIRT6 in glucose metabolism, although some survived beyond the early post-weaning period. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Zhong L, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140:280–293. doi: 10.1016/j.cell.2009.12.041. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Results

    Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation because of enhanced glycolysis and triglyceride synthesis.

    “Interestingly, it has also been recently reported that hepatic-specific disruption of SIRT6 in mice results in fatty liver formation because of enhanced glycolysis and triglyceride synthesis (27).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Kim HS, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 2010;12:224–236. doi: 10.1016/j.cmet.2010.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Results

    IRS2 is a cytoplasmic signaling molecule that mediates the effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between receptor tyrosine kinases and downstream effectors.

    “IRS2 is a cytoplasmic signaling molecule that mediates the effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between receptor tyrosine kinases and downstream effectors (21–23).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [21] Haeusler RA, Accili D. The double life of Irs. Cell Metab. 2008;8:7–9. doi: 10.1016/j.cmet.2008.06.010. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The paper’s opening passage describes Irs1 and Irs2 as insulin-signaling adaptors that act downstream of insulin and IGF receptors to engage other signaling components. The Liver Conundrum section also describes Irs2 mediating insulin action. Our copy does not establish the claim’s additional assertion that Irs2 mediates the effects of other cytokines. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Thirone AC, Huang C, Klip A. Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab. 2006;17:72–78. doi: 10.1016/j.tem.2006.01.005. [DOI] [PubMed] [Google Scholar] source
    • cites [23] White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 2002;283:E413–E422. doi: 10.1152/ajpendo.00514.2001. [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Discussion

    miR-33a and Srebp-2 are cotranscribed during states of cholesterol depletion.

    “Although our previous work established that miR-33a and Srebp-2 are cotranscribed during states of cholesterol depletion (14)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § Discussion

    During sterol-limited states, miR-33a is coincidentally generated with Srebp-2 transcription and works to increase cellular cholesterol levels by limiting cholesterol export through down-regulation of ABC transporters, ABCA1 and ABCG1.

    “We and others have recently established that, during sterol-limited states, miR-33a is coincidentally generated with Srebp-2 transcription and works to increase cellular cholesterol levels by limiting cholesterol export through the down-regulation of ABC transporters, ABCA1 and ABCG1 (12–14).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [12] Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107:12228–12232. doi: 10.1073/pnas.1005191107. [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [13] Najafi-Shoushtari SH, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–1569. doi: 10.1126/science.1189123. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results report that cholesterol depletion increased both miR-33a and its SREBP-2 host gene in mouse macrophages, while reducing ABCA1 protein. They also show that miR-33a reduced cholesterol efflux and promoted intracellular cholesterol retention through ABCA1 repression. The passages do not support the additional claim that miR-33a down-regulates ABCG1. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The passages labeled Abstract report that miR-33 rises alongside SREBF2 during cholesterol depletion and represses cholesterol export through ABCA1. They also show ABCG1 repression in mouse cells, but state that human ABCG1 lacks miR-33 binding sites. The claim does not qualify its ABCG1 statement by species, despite referring specifically to miR-33a. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Findingcitation
    § Discussion

    Changes in Srebp-2 and miR-33a transcription were quite small in the setting of cholesterol depletion.

    “Although our previous work established that miR-33a and Srebp-2 are cotranscribed during states of cholesterol depletion (14), the changes in Srebp-2 and miR-33a transcription were quite small in this setting.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Rayner KJ, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–1573. doi: 10.1126/science.1189862. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Discussion

    Srebp-1c is transcribed at extremely high levels in response to insulin.

    “By contrast, Srebp-1c is transcribed at extremely high levels in response to insulin (6, 28)”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [6] Horton JD, Goldstein JL, Brown MS. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–1131. doi: 10.1172/JCI15593. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The sections “Transcriptional regulation of SREBP genes” and “SREBP-1c and the insulin/glucagon ratio” say that insulin regulates SREBP-1c transcription and increases its mRNA in rat hepatocytes. They do not establish that it is transcribed at “extremely high levels”; no page number is available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [28] Brown MS, Ye J, Goldstein JL. Medicine. HDL miR-ed down by SREBP introns. Science. 2010;328:1495–1496. doi: 10.1126/science.1192409. [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • May combine two claims.

    Findingown data
    § Abstract

    Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines.

    “Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IRS2 is an essential component of the insulin-signaling pathway in the liver.

  • May combine two claims.

    Findingown data
    § Abstract

    Inhibition of endogenous miR-33a and -b increases fatty acid oxidation and insulin signaling.

    “whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IRS2 is an essential component of the insulin-signaling pathway in the liver.

  • May combine two claims.

    Findingown data
    § Results

    miR-33b regulates CROT, CPT1a, HADHB, AMPKα, and IRS2 at the protein level.

    “Similar regulation of these genes by miR-33b was also seen at the protein level (Fig. 1 C and D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In HepG2 cells, miR-33b overexpression down-regulated CROT, CPT1a, and AMPKα, but did not change expression of non-miR-33 targets.

    “Whereas CROT, CPT1a, and AMPKα were predictably down-regulated by miR-33, we did not observe changes in the expression of non–miR-33 targets (Fig. 1E).”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Results

    FRS2 is a predicted target of miR-33a and -b.

    “Interestingly, FRS2 is also a predicted target of miR-33a and -b.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    miR-33b overexpression inhibits expression of GCK, FRS2, ACACA, and PPARG in Huh7 cells.

    “Moreover, glucokinase (GCK), fibroblast growth factor receptor substrate 2 (FRS2), acetyl-CoA carboxylase-α (ACACA), and peroxisome proliferator-activated–γ (PPARG) were also inhibited (Fig. 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Other genes containing putative miR-33 binding sites such as CS and HMGCR were not affected at the mRNA level or by 3′ UTR activity.

    “Furthermore, other genes containing putative miR-33 binding sites such as citrate synthase (CS) and HMGCR were not affected either at the mRNA level (Fig. S5A) or by 3′ UTR activity (Fig. S5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Mutation of the miR-33 target sites in Crot, Cpt1a, Hadhb, Ampkα, and Irs2 3′ UTR constructs relieved miR-33b repression, consistent with a direct interaction of miR-33b with these sites.

    “Furthermore, mutation of the miR-33 target sites in these constructs relieved miR-33b repression of the 3′ UTR of Crot, Cpt1a, Hadhb, Ampkα, and Irs2, consistent with a direct interaction of miR-33b with these sites (Fig. S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In Huh7 cells, insulin induces FoxO1-GFP translocation from the nucleus to the cytoplasm in control cells, whereas miR-33b overexpression reverses this distribution.

    “Treatment with insulin induced FoxO1-GFP translocation from the nucleus to the cytoplasm in Con-miR–transfected cells (Fig. S7A Lower), whereas cells transfected with miR-33b had the cellular distribution reversed (Fig. S7B Lower).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    Antagonism of endogenous miR-33a and -b up-regulates fatty acid oxidation and response to insulin in hepatocytes.

    “Importantly, we show that antagonism of endogenous miR-33a and -b up-regulates fatty acid oxidation and response to insulin in hepatocytes”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Results

    FoxO1 is a well-defined target downstream of the conserved insulin/TOR signaling network that has important roles in the regulation of cellular growth, stress resistance, and energy homeostasis.

    “FoxO1 is a well-defined target downstream of the conserved insulin/target of rapamycin (TOR) signaling network that has important roles in the regulation of processes as diverse as cellular growth, stress resistance, and energy homeostasis (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421–426. doi: 10.1016/s0092-8674(04)00452-0. [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Results

    CROT catalyzes the reversible transfer of fatty acyl between CoA and carnitine and provides a crucial step in the transport of medium and long-chain acyl-CoA out of the peroxisome to the cytosol and mitochondria.

    “CROT, a carnitine acyltransferase that catalyzes the reversible transfer of fatty acyl between CoA and carnitine, provides a crucial step in the transport of medium and long-chain acyl-CoA out of the mammalian peroxisome to the cytosol and mitochondria (17–20).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [17] Brady PS, Ramsay RR, Brady LJ. Regulation of the long-chain carnitine acyltransferases. FASEB J. 1993;7:1039–1044. doi: 10.1096/fasebj.7.11.8370473. [DOI] [PubMed] [Google Scholar] source
    • cites [18] Eaton S, et al. The mitochondrial trifunctional protein: Centre of a beta-oxidation metabolon? Biochem Soc Trans. 2000;28:177–182. doi: 10.1042/bst0280177. [DOI] [PubMed] [Google Scholar] source
    • cites [19] Mannaerts GP, Van Veldhoven PP, Casteels M. Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals. Cell Biochem Biophys. 2000;32:73–87. doi: 10.1385/cbb:32:1-3:73. [DOI] [PubMed] [Google Scholar] source
    • cites [20] Ramsay RR, Gandour RD. Selective modulation of carnitine long-chain acyltransferase activities. Kinetics, inhibitors, and active sites of COT and CPT-II. Adv Exp Med Biol. 1999;466:103–109. [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Results

    AMPKα stimulates hepatic fatty acid oxidation and ketogenesis.

    “AMPKα stimulates hepatic fatty acid oxidation and ketogenesis (17–20).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [17] Brady PS, Ramsay RR, Brady LJ. Regulation of the long-chain carnitine acyltransferases. FASEB J. 1993;7:1039–1044. doi: 10.1096/fasebj.7.11.8370473. [DOI] [PubMed] [Google Scholar] source
    • cites [18] Eaton S, et al. The mitochondrial trifunctional protein: Centre of a beta-oxidation metabolon? Biochem Soc Trans. 2000;28:177–182. doi: 10.1042/bst0280177. [DOI] [PubMed] [Google Scholar] source
    • cites [19] Mannaerts GP, Van Veldhoven PP, Casteels M. Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals. Cell Biochem Biophys. 2000;32:73–87. doi: 10.1385/cbb:32:1-3:73. [DOI] [PubMed] [Google Scholar] source
    • cites [20] Ramsay RR, Gandour RD. Selective modulation of carnitine long-chain acyltransferase activities. Kinetics, inhibitors, and active sites of COT and CPT-II. Adv Exp Med Biol. 1999;466:103–109. [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Results

    SREBP in flies regulates fatty acid metabolism.

    “SREBP in flies regulates fatty acid metabolism (16), which is reminiscent of the function of the Srebp-1 gene in mammals (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Rawson RB. The SREBP pathway—insights from Insigs and insects. Nat Rev Mol Cell Biol. 2003;4:631–640. doi: 10.1038/nrm1174. [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Results

    CPT1a mediates the transport of long fatty acids across the mitochondrial membrane by binding them to carnitine and is the rate-limiting enzyme that regulates fatty acid oxidation.

    “CPT1a is a mitochondrial enzyme that mediates the transport of long fatty acids across the membrane by binding them to carnitine, and it is the rate-limiting enzyme that regulates fatty acid oxidation (17–20).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [17] Brady PS, Ramsay RR, Brady LJ. Regulation of the long-chain carnitine acyltransferases. FASEB J. 1993;7:1039–1044. doi: 10.1096/fasebj.7.11.8370473. [DOI] [PubMed] [Google Scholar] source
    • cites [18] Eaton S, et al. The mitochondrial trifunctional protein: Centre of a beta-oxidation metabolon? Biochem Soc Trans. 2000;28:177–182. doi: 10.1042/bst0280177. [DOI] [PubMed] [Google Scholar] source
    • cites [19] Mannaerts GP, Van Veldhoven PP, Casteels M. Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals. Cell Biochem Biophys. 2000;32:73–87. doi: 10.1385/cbb:32:1-3:73. [DOI] [PubMed] [Google Scholar] source
    • cites [20] Ramsay RR, Gandour RD. Selective modulation of carnitine long-chain acyltransferase activities. Kinetics, inhibitors, and active sites of COT and CPT-II. Adv Exp Med Biol. 1999;466:103–109. [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Results

    HADHB is the β-subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial β-oxidation of long-chain fatty acids.

    “HADHB is the β-subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial β-oxidation of long-chain fatty acids”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [17] Brady PS, Ramsay RR, Brady LJ. Regulation of the long-chain carnitine acyltransferases. FASEB J. 1993;7:1039–1044. doi: 10.1096/fasebj.7.11.8370473. [DOI] [PubMed] [Google Scholar] source
    • cites [18] Eaton S, et al. The mitochondrial trifunctional protein: Centre of a beta-oxidation metabolon? Biochem Soc Trans. 2000;28:177–182. doi: 10.1042/bst0280177. [DOI] [PubMed] [Google Scholar] source
    • cites [19] Mannaerts GP, Van Veldhoven PP, Casteels M. Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals. Cell Biochem Biophys. 2000;32:73–87. doi: 10.1385/cbb:32:1-3:73. [DOI] [PubMed] [Google Scholar] source
    • cites [20] Ramsay RR, Gandour RD. Selective modulation of carnitine long-chain acyltransferase activities. Kinetics, inhibitors, and active sites of COT and CPT-II. Adv Exp Med Biol. 1999;466:103–109. [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premiseown data
    § Results

    miR-33a and -b have identical seed sequences but differ in 2 of 19 nt of the mature RNA.

    “miR-33a and -b have identical seed sequences but differ in 2 of 19 nt of the mature RNA (Fig. S1C).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given
    § Materials and Methods

    Quantitative values represent averages from at least 30 cells per well.

    “All quantitative values represent averages from at least 30 cells per well.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Materials and Methods

    Data are the mean ± SEM and are representative of three independent experiments.

    “Data are the mean ± SEM and are representative of three independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data
    § Discussion

    miR-33a and -b may be an attractive therapeutic target for metabolic syndrome.

    “suggesting that miR-33a and -b may be an attractive therapeutic target for metabolic syndrome.”
    Quote in the paperNot a substantial claim
35 of 35

  • The paper relies on this without support.

    IRS2 is an essential component of the insulin-signaling pathway in the liver.

    “Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver.”

  • The paper relies on this without support.

    The Srebp1 genes of rats and mice lack miR-33b.

    “because the Srebp1 genes of these animal models lack miR-33b.”

  • The paper relies on this without support.

    AKT/PKB phosphorylates FoxO in three conserved sites, leading to FoxO cytoplasmic retention and transcriptional inactivation.

    “One of the best documented is the AKT/protein kinase B (PKB) kinase, which phosphorylates FoxO in three conserved sites, leading to FoxO cytoplasmatic retention and transcriptional inactivation.”

  • The paper relies on this without support.

    The Srebp gene of Drosophila controls fatty acid production.

    “Interestingly, the Srebp gene of Drosophila controls fatty acid production”

  • The paper relies on this without support.

    Drosophila neither synthesizes sterols nor expresses ABCA1.

    “because Drosophila neither synthesizes sterols nor expresses ABCA1.”
5 of 5

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?

  • miR-33 represses IRS2, PRKAA1, and SIRT6, genes important for maintenance of insulin sensitivity, cellular energy balance, and mitochondrial function.

    “It represses insulin receptor substrate 2 (IRS2), protein kinase AMP-activated catalytic subunit a1 (PRKAA1), and sirtuin 6 (SIRT6) 34 , 35) , genes that are important for the maintenance of insulin sensitivity, cellular energy balance, and the mitochondrial function.”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [34]

    The Results report that miR-33 represses IRS2, AMPKα and SIRT6, and describe their roles in insulin signaling, fatty acid oxidation and glucose metabolism. The copy discusses mitochondrial fatty acid oxidation, but does not establish that these three genes maintain mitochondrial function as the citing sentence states. No page numbers are provided in the indexed passages. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • miR-33a and miR-33b are co-transcribed along with SREBP-2 and SREBP-1 and work in concert with their host genes to help maintain proper lipid levels within the cell.

    “This work led to the demonstration that miR-33a and miR-33b are co-transcribed along with SREBP-2 and SREBP-1, and work in concert with their host genes to help maintain proper lipid levels within the cell (Davalos et al., 2011; Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”

    From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Davalos et al., 2011

  • miR-33a and miR-33b help prevent further loss of lipids by targeting genes involved in cholesterol trafficking and efflux and fatty acid β-oxidation.

    “miR-33a and miR-33b help prevent further loss of lipids by targeting genes involved in cholesterol trafficking and efflux”

    From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Davalos et al., 2011

  • miR-33 suppresses genes involved in mitochondrial β-oxidation, such as CPT1A, HADHB, and CROT.

    “MiR-33 suppresses genes involved in mitochondrial β-oxidation, such as carnitine palmitoyltransferase 1A (CPT1A), hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit b (HADHB), and carnitine O-octanoyltransferase (CROT) 15 , 17 , 34 , 35) .”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [34]

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.

  • Oleate incubation is reported as both 24 and 12 hours

    Major

    The results describe Huh7 cells incubated with oleate for 24 hours before starvation, whereas the immunohistochemistry method describes 12 hours before the same 24-hour starvation period.

1 of 1

Cites

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Related

Authors
Dávalos, A., Goedeke, L., Smibert, P., Ramírez, C. M., Warrier, N. P., Andreo, U., Cirera-Salinas, D., Rayner, K., Suresh, U., Pastor-Pareja, J. C., Esplugues, E., Fisher, E. A., Penalva, L. O. F., Moore, K. J., Suárez, Y., Lai, E. C., & Fernández-Hernando, C.
Affiliations
  • NYU Langone Health (US)
  • Department of Developmental Biology, Sloan–Kettering Institute, New York, NY 10065;
  • Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY 10016;
  • The University of Texas at San Antonio Health Science Center (US)
  • Yale University (US)
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2011-05-16
Volume
108
Issue
22
Pages
9232-9237
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1102281108
PMC
PMC3107310
OpenAlex
W2030354790
Semantic Scholar
4a7c3442c0dc1e42524b4ece3797a409b5d0dd26
Cited by
670
References
38
Citations by year
2026: 15 · 2025: 23 · 2024: 24 · 2023: 46 · 2022: 35 · 2021: 48 · 2020: 49 · 2019: 32 · 2018: 45 · 2017: 39 · 2016: 64 · 2015: 56 · 2014: 71 · 2013: 60 · 2012: 52
FWCI
19.00
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • American Heart Association
  • Deutsche Forschungsgemeinschaft (EXC257)
  • National Institutes of Health (5r01ag020255-10, 2r01gm083300-18)
  • National Institute on Aging (R01AG20255, R01-AG020255)
  • National Heart, Lung, and Blood Institute (R01 HL58541, R01HL16063, P30HL101270, R01HL058541, R01HL107953)
  • National Institute of General Medical Sciences (R01-GM083300)
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, fatty acid oxidation, insulin signaling, insulin receptor substrate 2, SIRT6, AMPK, CPT1A, hydroxyacyl-CoA dehydrogenase, SREBP, cholesterol homeostasis, metabolic syndrome, atherosclerosis, HDL cholesterol, triglycerides, liver, miRNA inhibitors
MeSH terms
Animals, Cardiovascular Diseases, Cholesterol, Cytoplasm, Drosophila melanogaster, Fatty Acids, Homeostasis, Humans, Immunohistochemistry, Insulin, Lipids, Phosphorylation, RNA Processing, Post-Transcriptional, Signal Transduction, MicroRNAs

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 2026-10-21.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-21.

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