The DOI matches its Crossref record; 37 of the 38 references it cites were found in a registry or an index; 31 of the 69 sources its claims cite were checked for support.
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
48 Own result · 15 Own interpretation · 10 Partly supported · 6 Not checked yet · 4 Supported · 4 Supported so far · 2 No full text of the sources · 2 Own method · 1 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
What the sources say
- Supportedcites [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 Discussion (page not specified) reports that SIRT6 modulates glucose homeostasis: SIRT6-deficient mice had enhanced glucose uptake and severe hypoglycemia. The cited paper supports SIRT6’s role in glucose homeostasis; the miR-33 target prediction is explicitly attributed to the citing authors’ own bioinformatic analysis. (LLM, conf=0.90)
- Supportedcites [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
The Introduction and Discussion identify SIRT6 as a histone deacetylase that regulates glucose homeostasis. The bioinformatic prediction that SIRT6 is a miR-33 target is the citing authors’ own finding, not a finding attributed to this source. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although our previous work in mice supports this contention by showing that inhibition of miR-33a and -b effectively increases HDL (14)”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Importantly, these pathways regulate circulating HDL levels through their roles in HDL biogenesis and cellular cholesterol efflux (12–14).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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 inhibiting miR-33 increased cholesterol efflux from macrophages and significantly raised plasma HDL-cholesterol in mice. They also describe ABCA1-dependent cholesterol efflux and HDL biogenesis as parts of the miR-33/SREBP/ABCA1 regulatory circuit. (LLM, conf=0.90)
- Supportedcites [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 explicitly identifies HDL biogenesis in the liver and cellular cholesterol efflux as two pathways that control HDL cholesterol. It also reports that manipulating miR-33 changes circulating HDL levels in mice. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [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 — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked yetcites [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]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling.”
- Also stated in: § Abstract · plain
“In addition to this role in maintaining cholesterol homeostasis, we now show that miR-33a and -b also regulate fatty acid metabolism and insulin signaling.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: IRS2 is an essential component of the insulin-signaling pathway in the liver.
- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Kinetic analysis of miR-33b induction revealed a concomitant increase in miR-33b and SREBP-1c expression, consistent with their coregulation.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Fig. S1 A and B, miR-33b is synchronously expressed with SREBP-1c in human hepatic Huh7 cells treated with an agonist of the liver X receptor (LXR), a transcriptional regulator of Srebp-1c expression.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, we show that miR-33a and miR-33b have overlapping gene targets”
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 23
- It may state two separate claims as one. 20
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“a class of noncoding RNAs, termed microRNAs (miRNAs), has emerged as critical regulators of gene expression acting predominantly at the posttranscriptional level (8–10).”
What the sources say
- Not checked — no full text of the sourcecites [8] Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–355. doi: 10.1038/nature02871. [DOI] [PubMed] [Google Scholar] source
- Supportedcites [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
The Abstract describes miRNAs as having important gene-regulatory roles through posttranscriptional repression of mRNAs. The section “The miRNAs” further explains that they commonly repress translation, destabilize mRNAs, or both. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In mice, however, there is only one miR-33 gene, which is conserved with human miR-33a and located within intron 15 of the mouse Srebp-2 gene.”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Supportedcites [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 passage [1] explicitly says that mice have only one miR-33 isoform, conserved with human miR-33a, located in intron 15 of the mouse SREBP-2 gene. This matches the attributed claim. (LLM, conf=0.95)
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“SREBP-1c regulates the transcription of genes involved in fatty acid metabolism, such as fatty acid synthase (FASN) (5–7).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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 section “SREBPs: two genes, three proteins” identifies fatty acid synthase (FASN) among SREBP-1c-responsive genes in the fatty acid biosynthetic pathway. The “SREBPs in liver: unanswered questions” section also discusses transcriptional activation of FASN in concert with SREBPs. (LLM, conf=0.94)
- Supportedcites [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
In “Key Role for SREBPs in Insulin Action and Lipogenesis” (page not available), the paper calls SREBP-1c a key transcriptional activator of lipogenesis and reports that blocking it prevented induction of FAS mRNA. This supports the claim that SREBP-1c regulates expression of fatty-acid-metabolism genes, including fatty acid synthase. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
In “SREBPs: two genes, three proteins,” the review identifies HMG-CoA reductase as an SREBP-2-responsive cholesterol-biosynthesis gene. “Function of individual SREBP isoforms in vivo” states that SREBP-2 preferentially activates the LDL receptor gene and genes required for cholesterol synthesis. Page numbers are not provided in our copy. (LLM, conf=0.94)
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We and others provided identification of a highly conserved miRNA family, miR-33, within the intronic sequences of the Srebp genes in organisms ranging from Drosophila to humans (11–14).”
What the sources say
- Supportedcites [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” places miR-33a and miR-33b in introns of the human SREBP genes and says the family's location and sequence are highly conserved down to insects. The section on Drosophila CPT1 explicitly identifies miR-33 as highly conserved in Drosophila. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [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
- Supportedcites [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 passage states that the authors noted a highly conserved miR-33 family within intronic sequences of SREBP genes in organisms from Drosophila to humans. It also identifies the introns containing the two human isoforms. (LLM, conf=0.95)
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“miRNA targeting of mRNAs inhibits their expression through mRNA destabilization, repression of translation, or a combination of both processes (8–10).”
What the sources say
- Not checked — no full text of the sourcecites [8] Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–355. doi: 10.1038/nature02871. [DOI] [PubMed] [Google Scholar] source
- Supportedcites [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
The section “The miRNAs” directly states that miRNAs pair with mRNAs to direct posttranscriptional repression and, more commonly, cause translational repression, mRNA destabilization, or both. This matches the claim. (LLM, conf=0.95)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The Abstract (page unavailable) states that SIRT6-deficient mice develop normally but die from lethal hypoglycemia early in life. The Results section on glucose uptake and the Discussion (pages unavailable) also describe the lethal hypoglycemia and SIRT6’s role in glucose homeostasis. (LLM, conf=0.95)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
What the sources say
- Supportedcites [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
The Abstract states that liver-specific deletion of SIRT6 in mice increases glycolysis and triglyceride synthesis and leads to fatty liver formation. The Discussion likewise identifies these changes as contributors to fatty liver, alongside other metabolic changes. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although our previous work established that miR-33a and Srebp-2 are cotranscribed during states of cholesterol depletion (14)”
What the sources say
- Supportedcites [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 paper identifies miR-33a as the human homolog of the mouse miR-33 it studies. It reports that cholesterol-depleted macrophages up-regulate both miR-33 and SREBF2, and explicitly describes their coincident transcription under low-sterol conditions (passages labeled Abstract; no page numbers supplied). (LLM, conf=0.93)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We and others have recently established that, during sterol-limited states, miR-33a is coincidentally generated with Srebp-2 transcription and works to increase cellular cholesterol levels by limiting cholesterol export through the down-regulation of ABC transporters, ABCA1 and ABCG1 (12–14).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
What the sources say
- Supportedcites [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 citation is attached to the statement that miR-33a and SREBF2 are cotranscribed during cholesterol depletion, not to the subsequent statement that their transcriptional changes were small. The passage labeled Abstract reports concomitant induction under cholesterol depletion, consistent with coregulation; it describes that increase as robust. The citing authors’ characterization of the changes as small is therefore not supported by this source, but is not the claim the citation is attached to. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“By contrast, Srebp-1c is transcribed at extremely high levels in response to insulin (6, 28)”
What the sources say
- Partly supportedcites [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] sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The passage labeled Abstract states that insulin enhances SREBP-1c transcription in the liver and that, when insulin levels are high, it is transcribed at extremely high levels. This directly supports the attributed claim in its hepatic context. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: IRS2 is an essential component of the insulin-signaling pathway in the liver.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: IRS2 is an essential component of the insulin-signaling pathway in the liver.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar regulation of these genes by miR-33b was also seen at the protein level (Fig. 1 C and D).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, FRS2 is also a predicted target of miR-33a and -b.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, we show that antagonism of endogenous miR-33a and -b up-regulates fatty acid oxidation and response to insulin in hepatocytes”
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked — no full text of the sourcecites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked yetcites [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]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“AMPKα stimulates hepatic fatty acid oxidation and ketogenesis (17–20).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked yetcites [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]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“SREBP in flies regulates fatty acid metabolism (16), which is reminiscent of the function of the Srebp-1 gene in mammals (6).”
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked yetcites [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]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked yetcites [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]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“miR-33a and -b have identical seed sequences but differ in 2 of 19 nt of the mature RNA (Fig. S1C).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All quantitative values represent averages from at least 30 cells per well.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data are the mean ± SEM and are representative of three independent experiments.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that miR-33a and -b may be an attractive therapeutic target for metabolic syndrome.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This work led to the demonstration that miR-33a and miR-33b are co-transcribed along with SREBP-2 and SREBP-1, and work in concert with their host genes to help maintain proper lipid levels within the cell (Davalos et al., 2011; Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Davalos et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Results
“We next evaluated the accumulation of neutral lipids and lipid droplet formation in Huh7 cells incubated with oleate for 24 h and then starved for the next 24 h.”
§ Materials and Methods
“Huh7 cells were transfected with miR-33 or Con-miR as described above and incubated with 1 mM oleate for 12 h. Then, cells were washed two times with cold PBS and starved for the next 24 h.”
Citations
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Self-citationEpigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field
Gallego‐Durán, R. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i24.2497 · Cited by 51
Autophagy in cardiovascular diseases: role of noncoding RNAs
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“For example, miR-33a/b is involved in the regulation of lipid metabolism.(137,138) Preclinical studies have shown that silencing miR-33 with anti-miR-33 in non-human primates can effectively reduce the plasma very-low-density lipoprotein (VLDL) and raise the high-density lipoprotein (HDL) level without significant sid…”
BackgroundPrice, N. L., Zhang, X., Fernández-Tussy, P., Singh, A. K., Burnap, S. A., Rotllan, N., Goedeke, L., Sun, J., Canfrán-Duque, A., Aryal, B., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2006478118 · Cited by 50
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“…shown to regulate cholesterol metabolism including miR-122-5p, miR-370-5p, miR-143-3p, miR-27-3p, miR-106b-5p, miR-758-5p, miR-144-3p and miR-33-5p (Davalos et al, 2011; de Aguiar Vallim et al, 2013; Elmen et al, 2008; Esau et al, 2006; Gerin et al, 2010; Goedeke et al, 2013; Horie et al, 2013;…”
BackgroundSelf-citationZhang, Y., Wang, H., Wang, Y., Wang, H., Zhang, S., Hong, J., Guo, H., Chen, D., Yang, Y., & Zan, L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185961 · Cited by 49
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miR-33a levels in hepatic and serum after chronic HBV-induced fibrosis
Huang, C., Sun, C., Zhao, F., Zhang, Y., & Li, D. (2014) · Journal of Gastroenterology · doi:10.1007/s00535-014-0986-3 · Cited by 47
“MicroRNA-33a (miR33a) recently has become a hot research small miRNA and it has been demonstrated that it not only regulate lipid homeostasis [18–21], but also may be exerting as a potent tumor suppressor [22], cell proliferation and cycling [23].”
BackgroundmicroRNAs and cancer metabolism reprogramming: the paradigm of metformin.
Pulito, C., Donzelli, S., Muti, P. C., Puzzo, L., Strano, S., & Blandino, G. (2014) · PubMed · doi:10.3978/j.issn.2305-5839.2014.06.03 · Cited by 49
“While Srebp1 and miR-33b regulate lipid homeostasis and insulin signaling by modulating the activity of key genes involved in these processes, Srebp2 and its intronic miRNA, miR-33a, regulate cholesterol homeostasis by modulating transcriptionally and post-transcriptionally the activity of genes involved in the cellul…”
BackgroundBiological roles of microRNAs in the control of insulin secretion and action
Caldérari, S., Diawara, M. R., Garaud, A., & Gauguier, D. (2016) · Physiological Genomics · doi:10.1152/physiolgenomics.00079.2016 · Cited by 50
“mir-33a/b Reduces liver fatty acid oxidation and insulin signaling; inhibits cholesterol cellular efflux; reduces plasma HDL and total cholesterol; reduces GSIS Liver, -cell Huh7, HEK293, MIN6 cells; J774 and THP-1 macrophages; adenoviral, lentiviral or LNA transduction; isolated islets Mouse, human (11, 48, 55, 69, 8…”
BackgroundNutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging
Micó, V., Berninches, L., Tapia, J., & Daimiel, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18050915 · Cited by 50
“Thus, miR-133 targets this pathway at two different points [99].”
BackgroundInsight into miRNAs related with glucometabolic disorder
Zhang, B., Shen, C., Zhu, B.-W., An, H., Zheng, B. J., Xu, S., Sun, J., Sun, P.-C., Zhang, W., Wang, J., et al. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.12.123 · Cited by 48
Gebreyesus, G., Buitenhuis, B., Poulsen, N. A., Visker, M. H. P. W., Zhang, Q., van Valenberg, H. J. F., Sun, D., & Bovenhuis, H. (2019) · BMC Genomics · doi:10.1186/s12864-019-5573-9 · Cited by 47
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“For instance, hepatic miR-33, miR-34a, miR-1224-5p, and miR-291b-3p are upregulated in NAFLD, resulting in deranged hepatic lipid metabolism and hepatic steatosis by repressing AMPK activity 13,19 e 21 .”
BackgroundTherapeutic Potential of Modulating microRNAs in Atherosclerotic Vascular Disease
Araldi, E., Chamorro-Jorganes, A., Solingen, C. V., Fernandez-Hernando, C. F., & Suárez, Y. (2015) · Current Vascular Pharmacology · doi:10.2174/15701611113119990012 · Cited by 47
Self-citationShen, B., Zhang, L., Lian, C., Lu, C., Zhang, Y., Pan, Q., Yang, R., & Zhao, Z. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020200 · Cited by 46
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“Additionally, we found that the levels of IRS-2, a central modulator of insulin signalling in normal and cancer cells and a target of microRNA33a as well [19] were modulated by metformin (Fig.”
Interplay Between Metabolism and Oncogenic Process: Role of microRNAs
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MicroRNAs and Circular RNAs in Lipoprotein Metabolism
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“Interestingly, its homologs in humans, hsa-miR-33a-5p and hsa-miR-33b-5p, are also located in SREBF-2 and SREBF-1, respectively, and they have been reported to control the insulin signaling pathway [38] and fatty acid metabolism in cooperation with the host gene [39].”
BackgroundInsights into the Regulatory Role of Non-coding RNAs in Cancer Metabolism
Beltrán‐Anaya, F. O., Cedro‐Tanda, A., Hidalgo‐Miranda, A., & Romero-Cordoba, S. L. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00342 · Cited by 44
“BRCA Xiang et al., 2014 lncRNA Lethe Induced by pro-inflammatory cytokines via NF-κB or glucocorticoid receptor agonists, and functions in a negative feedback signaling with NF-κB.”
BackgroundInfluentialThe miR‐181 family: Wide‐ranging pathophysiological effects on cell fate and function
Bell‐Hensley, A., Das, S., & McAlinden, A. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.30969 · Cited by 44
“While not directly related to adipocyte differentiation, multiple miRNAs have been validated to regulate fatty acid metabolism, insulin sensitivity, and dysregulate metabolic homeostasis that contribute to the development of obesity (Dávalos et al., 2011; Trajkovski et al., 2011).”
BackgroundMotiño, O., Francés, D. E., Mayoral, R., Castro‐Sánchez, L., Fernández‐Velasco, M., Boscá, L., García‐Monzón, C., Brea, R., Casado, M., Agrá, N., et al. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00198-15 · Cited by 43
“The relative amounts of each protein were determined with the following polyclonal or monoclonal antibodies: COX-2 (Cayman 160107 and Santa Cruz sc-1747); -tubulin (Sigma T9026); antiacetyllysine, p-IR, IRS1, and IRS2 (Millipore 06-933, 07-841, 06-248, and 06-506, respectively); DGCR8 (Proteintech 10996-1-AP); DDX5, D…”
BackgroundInfluentialMicroRNAs as the actors in the atherosclerosis scenario
Hajibabaie, F., Kouhpayeh, S., Mirian, M., Rahimmanesh, I., Boshtam, M., Sadeghian, L., Gheibi, A., Khanahmad, H., & Shariati, L. (2019) · Journal of physiology and biochemistry · doi:10.1007/s13105-019-00710-7 · Cited by 42
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MicroRNA regulation of cholesterol metabolism
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Self-citationAn Update in Epigenetics in Metabolic-Associated Fatty Liver Disease
Rodríguez-Sanabria, J. S., Escutia-Gutiérrez, R., Rosas-Campos, R., Armendáriz‐Borunda, J., & Sandoval-Rodriguez, A. S. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2021.770504 · Cited by 45
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Identification of microRNA that represses IRS-1 expression in liver
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“…et al., 2011). miRNAs widely participate in the activities of cells, such as cellular growth, differentiation (He et al., 2011; Sun and Lai, 2013), metabolism (Davalos et al., 2011), endoplasmic reticulum stress, oxidative stress, inflammation (Dudda et al., 2013; Nahid et al., 2013) and apoptosis.”
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“Accordingly, there is increased accumulation of TG and increased size of lipid droplets in cells overexpressing miR-33b (18).”
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HDL—A molecule with a multi-faceted role in coronary artery disease
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Implications of microRNAs in the pathogenesis of diabetes
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“These miRNAs also regulate various genes involved in fatty acid metabolism, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirt6, and AMP-activated protein kinase subunit-alpha (Davalos et al. 2011).”
BackgroundInfluentialMicroRNAs and lipoproteins: A connection beyond atherosclerosis?
Norata, G. D., Sala, F., Catapano, A. L., & Fernandez-Hernando, C. F. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.11.019 · Cited by 40
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“fatty acid metabolism (CROT and CPT1a) and insulin signaling (IRS2) [39,40].”
BackgroundPickering, C., & Kiely, J. (2019) · Journal of Functional Morphology and Kinesiology · doi:10.3390/jfmk4020025 · Cited by 48
“Additionally, lower concentrations of miR-33 are associated with greater activation of AMPK following aerobic training [102], and miR-29b alters PGC-1α production [103]—both molecular signals for mitochondrial biogenesis—again demonstrating how real-time monitoring of miRNA concentrations could allow coaches to unders…”
BackgroundLipid Disorders in NAFLD and Chronic Kidney Disease
Yang, M., Geng, C., Liu, X., & Guan, M. (2021) · Biomedicines · doi:10.3390/biomedicines9101405 · Cited by 44
Micromanaging metabolism—a role for miRNAs in teleost energy metabolism
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IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1−/− Mice Mediated by miR-33
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“It has been reported that miR-33a/b contributes to the regulation of fatty acid metabolism and insulin signaling (Davalos et al., 2011), and miR-503 inhibits adipogenesis through classical insulin signal of PI3K/AKT by targeting bone morphogenetic protein receptor 1a (Man et al.”
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“Furthermore, bta-miR-33a/b has been reported to contribute to the regulation of fatty acid metabolism and the insulin signaling pathway (Dávalos et al., 2011), which indicates that the insulin signaling pathway may be impacted in the H-OA group.”
BackgroundOkui, T., Iwashita, M., Rogers, M. A., Halu, A., Atkins, S. K., Kuraoka, S., Abdelhamid, I., Higashi, H., Ramsaroop, A., Aikawa, M., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.315007 · Cited by 41
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“The intronic miRNAs hsa-miR-33a and hsa-miR-33b located within Srebp2 and Srebp1 genes, respectively, regulate cholesterol metabolism and modulate fatty acid β-oxidation and insulin signaling in the liver, which may be particularly relevant in the setting of metabolic syndrome [39].”
BackgroundLi, C., Liu, C., Zhang, J., Lu, Y., Jiang, B., Xiong, H., & Li, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1296687 · Cited by 42
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Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33
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“In human, miR-122 is a key regulator of cholesterol and fatty acid metabolism in the adult liver [31], while miR-33a/b is the regulator of fatty acid metabolism and insulin signaling [32].”
BackgroundDiabetes in Pregnancy and MicroRNAs: Promises and Limitations in Their Clinical Application
Ibarra, A., Guedes, B. V., Brito‐Casillas, Y., & Wägner, A. M. (2018) · Non-Coding RNA · doi:10.3390/ncrna4040032 · Cited by 39
“MiR-33b and miR-375 are related to the metabolism of glucose and lipids and insulin signalling or secretion [49,50,133], whereas miR-454-3p has a role in inflammatory response and postnatal brain development [134,135].”
BackgroundMicroRNAs as a Novel Tool in the Diagnosis of Liver Lipid Dysregulation and Fatty Liver Disease
Yu, J., Peng, J., Luan, Z., Zheng, F., & Su, W. (2019) · Molecules · doi:10.3390/molecules24020230 · Cited by 40
“miR-24 Human, Mouse NAFLD ↑ Insig1 Downregulate Insig1 expression; Promote SREBP-1 processing − [72]”
BackgroundPosttranscriptional Regulation of Insulin Resistance: Implications for Metabolic Diseases
Pérez-García, A., Torrecilla-Parra, M., Frutos, M. F.-D., Martín-Martín, Y., Pardo, V., & Ramírez, C. M. (2022) · Biomolecules · doi:10.3390/biom12020208 · Cited by 45
Self-citationMicroRNA-33 in atherosclerosis etiology and pathophysiology
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“SLC25A25 Sapiens solute carrier family 25 [16,33,56]”
BackgroundInfluentialThe myriad essential roles of microRNAs in cardiovascular homeostasis and disease
Neppl, R. L., & Wang, D. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.06.003 · Cited by 36
Garbett, K. A., Vereczkei, A., Kalman, J. L., Wang, L., Korade, Ž., Shelton, R. C., & Mirnics, K. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.14 · Cited by 34
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“Increasingly, evidence indicates that sterol regulatory element-binding protein 2 (SREBP-2) and LDL receptor (LDL-R) are transcription factors involved in the regulation of cholesterol metabolism (13-15).”
Ma, E., Fu, Y., & Garvey, W. T. (2018) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2017.0101 · Cited by 37
Metformin and insulin-resistant related diseases: Emphasis on the role of microRNAs
Alimoradi, N., Firouzabadi, N., & Fatehi, R. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111662 · Cited by 39
The Role of miRNAs in Metabolic Diseases
Mačvanin, M., Obradovic, M. M., Zafirovic, S. S., Stanimirović, J., & Isenović, E. R. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220801161536 · Cited by 40
miR‐33 in cardiometabolic diseases: lessons learned from novel animal models and approaches
Price, N. L., Goedeke, L., Suárez, Y., & Fernández‐Hernando, C. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202012606 · Cited by 36
“…cell types and tissues and work together with their host genes to control lipid homeostasis (Gerin et al, 2010; Horie et al, 2010; Marquart et al, 2010; Najafi-Shoushtari et al, 2010; Rayner et al, 2010; Davalos et al, 2011; Goedeke et al, 2013; Shao et al, 2014; Shao et al, 2019; Zhu et al, 2020).”
BackgroundInfluentialSelf-citationArtimovič, P., Špaková, I., Macejková, E., Pribulová, T., Rabajdová, M., Mareková, M., & Závacká, M. (2024) · Genes and Immunity · doi:10.1038/s41435-024-00283-6 · Cited by 39
“In fl ammation during I/R upregulates miR-33 which targets AMPK, leading to a decrease in the intracellular availability of NAD + , thus negatively regulating SIRT1 activity [161 – 163].”
BackgroundWang, Y., Zhou, X., Shan, B., Han, J., Wang, F., Fan, X., Lv, Y., Chang, L., & Liu, W. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4296 · Cited by 36
“It is widely known that the miR-33 family has a critical role in cholesterol metabolism, fatty acid oxidation and regulation of insulin signaling (12,17,40,41).”
Zhang, Q., Xie, D., Wang, S., You, C., Monroig, Ó., Tocher, D. R., & Li, Y. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.03.009 · Cited by 37
CryomiRs: Towards the identification of a cold-associated family of microRNAs
Lyons, P. J., Lang-Ouellette, D., & Morin, P. (2013) · Comparative Biochemistry and Physiology Part D Genomics and Proteomics · doi:10.1016/j.cbd.2013.10.001 · Cited by 36
The Destiny of Glucose from a MicroRNA Perspective
Mirra, P., Nigro, C., Prevenzano, I., Leone, A., Raciti, G. A., Formisano, P., Bèguinot, F., & Miele, C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00046 · Cited by 40
microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function
Langlet, F., Tarbier, M., Haeusler, R. A., Camastra, S., Ferrannini, E., Friedländer, M. R., & Accili, D. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.08.003 · Cited by 38
“Several hepatic miRNAs, including miR-33 [13], miR-122 [14], miR103/107 [15], and miR-802 [16] have been shown to post-transcriptionally control expression of genes involved in metabolism and insulin signaling.”
BackgroundLuu, B. E., Lefai, É., Giroud, S., Swenson, J. E., Chazarin, B., Gauquelin‐Koch, G., Arnemo, J. M., Evans, A. L., Bertile, F., & Storey, K. B. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.29294 · Cited by 36
Post-lanosterol biosynthesis of cholesterol and cancer
Lasunción, M. A., Martín-Sánchez, C., Canfrán‐Duque, A., & Busto, R. (2012) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2012.07.001 · Cited by 36
MicroRNAs in Macrophages: Regulators of Activation and Function
Sprenkle, N. T., Serezani, C. H., & Pua, H. H. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200467 · Cited by 39
Why Targeting HDL Should Work as a Therapeutic Tool, but Has Not
Sorci‐Thomas, M. G., & Thomas, M. J. (2013) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e31829d48a5 · Cited by 35
“For example, overexpression of miR-33, a microRNA encoded by an intron of the gene for SREBP-2, has been shown to reduce the concentration of HDL-C through its suppression of sterol transporters and cholesterol homeostasis.(111,112) The lipid cargo may include a variety of oxidized lipids generated by reactive oxygen…”
BackgroundMicroRNA-33b downregulates the differentiation and development of porcine preadipocytes
Taniguchi, M., Nakajima, I., CHIKUNI, K., Kojima, M., Awata, T., & Mikawa, S. (2014) · Molecular Biology Reports · doi:10.1007/s11033-013-2954-z · Cited by 35
Hepatitis C virus and microRNAs: miRed in a host of possibilities
Singaravelu, R., Russell, R. S., Tyrrell, D. L., et al. (2014) · Current Opinion in Virology · doi:10.1016/j.coviro.2014.03.004 · Cited by 34
Non-coding RNAs in the development and pathogenesis of eukaryotic microbes
Chacko, N., & Lin, X. (2013) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-013-5160-y · Cited by 32
“The most common ncRNAs associatedwith cancer are themicro RNAs (miRNAs) (Davalos et al. 2011; Manel 2011).”
BackgroundCrucial genes associated with diabetic nephropathy explored by microarray analysis
Wang, Z., Wang, Z., Zhou, Z., & Ren, Y. (2016) · BMC Nephrology · doi:10.1186/s12882-016-0343-2 · Cited by 34
“MiR33a has been reported to be implicated in diabetes due to its regulation of insulin signaling and fatty acid metabolism [40, 41].”
BackgroundLim, E., Lim, J. Y., Kim, E., Kim, Y. S., Shin, J.-H., Seok, P. R., Jung, S., Yoo, S., & Kim, Y. (2016) · Nutrients · doi:10.3390/nu8120791 · Cited by 34
“Furthermore, based on the report that inhibition of miR-33a enhances FA oxidation and insulin signaling [51], the positive effects of XB on miR-33a may be related to improved insulin resistance.”
BackgroundMicroRNA-124 Regulates Fatty Acid and Triglyceride Homeostasis
Shaw, T. A., Singaravelu, R., Powdrill, M. H., Nhan, J., Ahmed, N., Özcelik, D., & Pezacki, J. P. (2018) · iScience · doi:10.1016/j.isci.2018.11.028 · Cited by 34
MicroRNAs isolated from peripheral blood in the first trimester predict spontaneous preterm birth
Winger, E. E., Reed, J. L., Ji, X., Gomez‐Lopez, N., Pacora, P., & Romero, R. J. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236805 · Cited by 36
“MiR-181a-3p is known to be dysregulated in the vascular endothelium of placental villi of unhealthy pregnancy, [68] miR-221-3p is dysregulated in peripheral blood of women with preeclampsia [69] and miR-33a is dysregulated women with metabolic syndrome [70, 71].”
BackgroundAre microRNAs the Molecular Link Between Metabolic Syndrome and Alzheimer’s Disease?
Codocedo, J. F., Ríos, J. A., Godoy, J. A., & Inestrosa, N. C. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9201-7 · Cited by 34
Liang, C., Wang, Z., Li, Y.-Y., et al. (2015) · Tumor Biology · doi:10.1007/s13277-015-3679-5 · Cited by 34
“phosphorylation, which is an important upstream molecule that regulates the stabilization of cytoplasmic β-catenin [27, 31].”
BackgroundPost-transcriptional regulation in metabolic diseases
Kim, W., & Lee, E. K. (2012) · RNA Biology · doi:10.4161/rna.20091 · Cited by 33
miRNAs in non-alcoholic fatty liver disease
He, Z., Hu, C., & Jia, W. (2016) · Frontiers of Medicine · doi:10.1007/s11684-016-0468-5 · Cited by 33
Mir-150 Up-Regulates Glut1 and Increases Glycolysis in Osteosarcoma Cells
Yuan, G., Zhao, Y., Wu, D., et al. (2017) · PubMed · doi:10.22034/apjcp.2017.18.4.1127 · Cited by 33
“miR-33a and miR-33b play critical roles in regulating cholesterol homeostasis and fatty acid degradation (Davalos et al., 2011), microRNA-495 regulates metabolic shift in glioma cells by targeting Glut1 (Nie et al.”
BackgroundPotential role for microRNA in regulating hypoxia-induced metabolic suppression in jumbo squids
Hadj‐Moussa, H., Logan, S. M., Seibel, B. A., & Storey, K. B. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2018.04.007 · Cited by 30
Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis
Borck, P. C., Batista, T. M., Vettorazzi, J. F., Soares, G. M., Lubaczeuski, C., Guan, D., Boschero, A. C., Vieira, E. C., Lazar, M. A., & Carneiro, E. M. (2018) · Metabolism · doi:10.1016/j.metabol.2018.05.002 · Cited by 33
“It has been shown that various miRNAs display a key role in the regulation of glucose and lipid metabolism, as well as insulin sensitivity [25, 26].”
BackgroundWan, N., Xu, Z., Chi, Q.-R., Hu, X.-Y., Pan, T., Liu, T., & Li, S. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28050 · Cited by 33
“…Ho, Chang, Chuang, & Wei, 2011; Rayner et al., 2011a), but it also participates in the regulation of other signaling pathways (Allen et al., 2012; Dávalos et al., 2011), such as the insulin signaling pathway (Nadeeja et al., 2012), as well as those involved in inflammatory reactions and cell…”
BackgroundZhang, Y., Xiang, D., Hu, X., et al. (2019) · Annals of Hepatology · doi:10.1016/j.aohep.2019.12.003 · Cited by 33
miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression
Benito‐Vicente, A., Uribe, K. B., Rotllán, N., Ramírez, C. M., Jebari‐Benslaiman, S., Goedeke, L., Canfrán‐Duque, A., Galicia-García, U., de Urturi, D. S., Aspichueta, P., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228675 · Cited by 34
Self-citationNon-Coding RNAs: Novel Players in Insulin Resistance and Related Diseases
Formichi, C., Nigi, L., Grieco, G. E., Maccora, C., Fignani, D., Brusco, N., Licata, G., Sebastiani, G., & Dotta, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147716 · Cited by 34
The role of noncoding RNAs in metabolic reprogramming of cancer cells
Safi, A., Saberiyan, M., Sanaei, M., Adelian, S., Asl, F. D., Zeinaly, M., Shamsi, M., & Ahmadi, R. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00447-8 · Cited by 36
“Recently Li et al. investigated two essential aspects of ORP8: oxysterol-binding protein-related protein 8; TS: tumor suppressor; UTR: untranslated region; IGF1-R: insulin-like growth factor 1 receptor; GLUT1: glucose transporter 1; CPT1A: carnitine palmitoyltransferase 1A; CPT1C: carnitine palmitoyltransferase 1C; CR…”
BackgroundInfluential‘Micro‐managers’ of hepatic lipid metabolism and NAFLD
Liu, W., Cao, H., Yan, J., Huang, R., & Ying, H. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1295 · Cited by 33
Expression of miR-33 from an SREBF2 Intron Targets the FTO Gene in the Chicken
Shao, F., Wang, X., Yu, J., Jiang, H., Zhu, B., & Gu, Z. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091236 · Cited by 33
“In addition to regulating cholesterol transport, high-density lipoprotein metabolism and fatty acid b-oxidation, miR-33 was recently reported to regulate cell cycle progression and cellular proliferation [12], inflammatory response [13] and insulin signaling [14].”
BackgroundMicroRNA regulation of AMPK in nonalcoholic fatty liver disease
Sun, H., & Kemper, J. K. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01072-3 · Cited by 35
Zhang, M., Gong, W., Zuo, B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12693 · Cited by 32
“miR-33a was first reported to inhibit fatty acid metabolism and insulin signaling [35].”
BackgroundSocial status affects lipid metabolism in rainbow trout,Oncorhynchus mykiss
Kostyniuk, D. J., Culbert, B. M., Mennigen, J. A., & Gilmour, K. M. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00402.2017 · Cited by 33
“These and other studies in mammalian models have also shown inhibitory roles for miRNA-33 in hepatic -oxidation by targeting enzymes involved in FA oxidation, including cpt1a (18, 32, 36).”
BackgroundMicroRNA-33/33* inhibit the activation of MAVS through AMPK in antiviral innate immunity
Liu, D., Tan, Q., Zhu, J., Zhang, Y., Xue, Y., Song, Y., Liu, Y., Wang, Q., & Lai, L. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0326-x · Cited by 32
Dallio, M., Romeo, M., Gravina, A. G., Masarone, M., Larussa, T., Abenavoli, L., Persico, M., Loguercio, C., & Federico, A. (2021) · Nutrients · doi:10.3390/nu13051679 · Cited by 32
“Besides miRNA-122, other miRNAs could interfere with these processes [96]: for instance, miRNA-33a/b action on the target AMPK, by reducing AMPK expression, increases the levels of intrahepatic TG [97]; contrariwise, miRNA-33a/b inhibition promotes beta-oxidation of FAs and insulin sensitivity [97,98].”
Background
Metadata
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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
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