Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation*
Open accessAbstract
The regulation of synthesis, degradation, and distribution of lipids is crucial for homeostasis of organisms and cells. The sterol regulatory element-binding protein (SREBP) transcription factor family is post-translationally activated in situations of reduced lipid abundance and activates numerous genes involved in cholesterol, fatty acid, and phospholipid synthesis. In this study, we provide evidence that the primary transcript of SREBP2 contains an intronic miRNA (miR-33) that reduces cellular cholesterol export via inhibition of translation of the cholesterol export pump ABCA1. Notably, miR-33 also inhibits translation of several transcripts encoding proteins involved in fatty acid β-oxidation including CPT1A, HADHB, and CROT, thereby reducing fatty acid degradation. The genetic locus encoding SREBP2 and miR-33 therefore contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly synthesized lipids. These results add an additional layer of complexity to our understanding of lipid homeostasis and might open possibilities for future therapeutic intervention.
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Written from the paper’s full text.
TL;DR
miR-33a is encoded in an intron of SREBP2 and directly represses ABCA1, CPT1A, HADHB, and CROT, thereby reducing cholesterol export and fatty acid β-oxidation while increasing cellular lipids. This bifunctional locus couples lipid synthesis with suppression of lipid export and degradation.
Key findings
- miR-33a localizes to an intron of SREBP2 and is evolutionarily conserved; reporter assays show it targets the ABCA1 3′ UTR, and seed-region mutations abolish this response.
- Overexpression of miR-33 reduces endogenous ABCA1 protein and apoAI-dependent cholesterol export in HepG2 and THP1 cells; miR-33 sponges and antagomirs increase ABCA1 protein and cholesterol export.
- miR-33 targets CPT1A, HADHB, and CROT 3′ UTRs; overexpression suppresses HADHB and CPT1A protein, reduces CROT mRNA, causes a 20% reduction in mitochondrial β-oxidation, and increases cellular free fatty acids and triacylglycerides.
- The Drosophila CPT1 3′ UTR contains a conserved functional miR-33 binding site, suggesting ancient regulation of β-oxidation.
Methods
- Reporter assays used luciferase constructs containing wild-type or mutated 3′ UTRs cotransfected with pre-miR-33 or control; lentiviral miR-33 overexpression, miRNA sponges, and antagomirs were tested in HepG2, THP1, Y1, and 293T cells, with Western blot, qPCR, and Northern blot readouts.
- Cholesterol export was measured using [1,2-3H]cholesterol and apoAI; β-oxidation was measured by conversion of [9,10-3H]palmitic acid to water in the presence or absence of etomoxir; lipids were analyzed by TLC.
- Male C57/BL6 mice were fed chow or a high-fat diet (60% calories from fat) for 16 weeks starting at 4 or 8 weeks of age; miR-33 levels were assessed by Northern blot. Analyses used normalized luciferase activity, Student’s t tests, and means ± S.D. or S.E.
Limitations
- Stated: no specific CROT Western blot was obtained; miR-33 inhibition did not reproducibly increase β-oxidation or HADHB/CPT1A protein in HepG2 cells; fasting and high-fat-diet mouse livers showed no significant miR-33 changes, with only a small non-significant trend toward lower levels on high-fat diet; preliminary TLC/gas chromatography did not support altered fatty acid chain lengths; future in vivo experiments are needed.
- Evident: many mechanistic conclusions rely on cell lines, overexpression, and reporter assays, so in vivo regulation and therapeutic relevance remain unestablished; several results are described as data not shown.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
19 of 43 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The dominant allosteric inhibitor malonyl-CoA regulates CROT similarly to CPT1A.
“Interestingly, the dominant allosteric inhibitor malonyl-CoA regulates CROT similarly to CPT1A (28,52).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [28] Saggerson, 2008, Annu. Rev. Nutr. source
- cites [52] A'Bháird, 1992, Biochem. J. source
In the 'Kinetics of COT assayed in peroxisomes' section, the paper says malonyl-CoA inhibits peroxisomal COT more selectively than other short-chain acyl-CoA esters and that features of this inhibition resemble CPT-I. It does not establish that the inhibition is allosteric: a separate regulatory binding site is proposed as a possibility, while inhibition of purified COT is described as competitive. Page numbers were not supplied with these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Reduced gene dosage or activity of the mitochondrial trifunctional protein complex leads to the accumulation of lipids in the liver (hepatic steatosis).
“Surprisingly, there is evidence that reduced gene dosage or activity of this enzyme complex leads to the accumulation of lipids in the liver (hepatic steatosis) (32,33).”
Quote in the paperNot a substantial claim2 of 2 sources checked - Findingown data
miR-33 suppresses HADHB and CPT1A protein levels in HepG2 cells.
“As shown in Fig. 6A, miR-33 suppresses HADHB and CPT1A protein levels.”
Quote in the paperSubstantial claim- Rests on an assumption: The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
- Rests on an assumption: The antibodies used for Western blot analysis specifically detect their intended targets (ABCA1, HADHB, CPT1A, HADHA, GAPDH, and β-actin).
- Findingown data
Overexpression of miR-33 reduces mitochondrial β-oxidation by 20%.
“As shown in Fig. 6C, overexpression of miR-33 is associated with a 20% reduction of mitochondrial -oxidation.”
Quote in the paperSubstantial claim- Rests on an assumption: The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
- Findingown data
miR-33a is localized in an intron of the human SREBP2 gene.
“miR-33a and miR-33b are localized in corresponding introns of the human SREBP2 and SREBP1 genes, respectively (Fig. 1A and supplemental Fig. S3).”
Quote in the paperSubstantial claim
- Findingown data
Doxycyclin-induced expression of miR-33a in THP1 cells reduces ABCA1 protein levels.
“the cell line transduced with the conditional miR-33a lentivirus shows strong reduction of ABCA1 levels upon treatment with doxycyclin (Fig. 4A, fifth to eighth lanes).”
Quote in the paperSubstantial claim- Rests on an assumption: The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
- Findingown data
miR-33 reduces cellular cholesterol export.
“we loaded cells with radioactively labeled cholesterol, and observed significantly reduced apoAI-dependent cholesterol export in the HepG2 liver cancer cell line (Fig. 3B) and THP1 monocytic leukemia cell line derived from macrophages (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
CROT mRNA levels are significantly reduced in cell lines overexpressing miR-33.
“As shown in Fig. 6B, CROT mRNA levels were significantly reduced in cell lines overexpressing miR-33 to a degree that is similar to the reduction of ABCA1 and CPT1A”
Quote in the paperSubstantial claim- Rests on an assumption: The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
- Findingown data
miR-33a expression decreases endogenous ABCA1 protein levels in HepG2 cells.
“We observed that miR-33a causes a marked decrease of ABCA1 protein levels (Fig. 3A, lanes 1 and 2) as assessed by immunoblot analysis.”
Quote in the paperSubstantial claim- Rests on an assumption: The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
- Rests on an assumption: The antibodies used for Western blot analysis specifically detect their intended targets (ABCA1, HADHB, CPT1A, HADHA, GAPDH, and β-actin).
- Findingown data
miR-33a directly targets the ABCA1 3' UTR.
“Cotransfection of preMIR-33a significantly reduced the activity of the reporter construct containing the 3Ј UTR of ABCA1 (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
miR-33a and miR-33b are localized in corresponding introns of the human SREBP2 and SREBP1 genes, respectively.
“miR-33a and miR-33b are localized in corresponding introns of the human SREBP2 and SREBP1 genes, respectively (Fig. 1A and supplemental Fig. S3).”
Quote in the paperSubstantial claim - Findingown data
miR-33 expression reduces apoAI-dependent cholesterol export in HepG2 and THP1 cells.
“we loaded cells with radioactively labeled cholesterol, and observed significantly reduced apoAI-dependent cholesterol export in the HepG2 liver cancer cell line (Fig. 3B) and THP1 monocytic leukemia cell line derived from macrophages (Fig. 4B).”
Quote in the paperSubstantial claim- Rests on an assumption: The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
- Findingown data
Antagomir-33 transfection into HepG2 cells stimulates apoAI-dependent cholesterol export.
“When antagomir 33 was transfected into HepG2 cells, an even more dramatic stimulation of apoAI-dependent cholesterol export was observed (Fig. 3, E and F).”
Quote in the paperSubstantial claim- Rests on an assumption: The miRNA sponges and antagomirs specifically inhibit miR-33 without off-target effects.
- Findingnone given
The miR-33 binding site in CPT1A is localized quite distant from the open reading frame.
“Third, in the case of CPT1A, it should also be noted that the miR-33 binding site is localized quite distant from the open reading frame.”
Quote in the paperNot a substantial claim - Findingreasoning
Strong reduction of HADHB in HepG2 is accompanied by a reduction in HADHA.
“In line with these observations, the strong reduction of HADHB in HepG2 was accompanied by a reduction in HADHA.”
Quote in the paperNot a substantial claim - Findingown data
miR-33a is predicted to bind the 3' UTR of the human HADHB transcript.
“A, predicted binding of miR-33a to the 3Ј UTR of the human HADHB transcript.”
Quote in the paperSubstantial claim - Findingown data
Deletion of the nonconserved predicted binding site 1 of CPT1A does not affect regulation by miR-33.
“For example, deletion of the nonconserved predicted binding site 1 of the CPT1A transcript did not affect regulation by miR-33.”
Quote in the paperNot a substantial claim - Findingown data
Extending annotated gene transcripts with expressed sequence tags reveals that CPT1A in Xenopus tropicalis and Ciona intestinalis contain miR-33 seed binding sites.
“Extending annotated gene transcripts with expressed sequence tags reveals that CPT1A in the frog Xenopus tropicalis and even the primitive chordate Ciona intestinalis (sea squirt) contain miR-33 seed binding sites (supplemental Fig. S7, C and D).”
Quote in the paperSubstantial claim - Findingown data
When cloned behind a constitutively active firefly luciferase expression cassette, the Drosophila CPT1 3' UTR element confers responsiveness to miR-33 in reporter assays.
“When cloned behind a constitutively active firefly luciferase expression cassette, this element confers responsiveness to miR-33 in reporter assays (Fig. 7B).”
Quote in the paperSubstantial claim - Findingown data
miR-33a is predicted to bind the 3' UTR of the human CPT1A transcript encoding the rate-limiting step of cellular β-oxidation.
“E, predicted binding of miR-33a to the 3Ј UTR of the human CPT1A transcript encoding the rate-limiting step of cellular -oxidation.”
Quote in the paperSubstantial claim - Findingown data
In livers of fasting mice and in two cohorts of mice exposed to a high fat diet for 16 weeks, there is no significant alteration of miR-33 expression levels.
“In the livers of fasting mice and in two separate cohorts of mice exposed to a high fat diet for 16 weeks, we did not observe any significant alteration of miR-33 expres- sion levels, albeit there was a small but non-significant trend for the high-fat diet group toward lower miR-33 levels (supple- mental Fig. S12, B-D).”
Quote in the paperNot a substantial claim - Findingown data
The transcript of Drosophila CPT1 contains a predicted miR-33 binding site in its 3' UTR that is completely conserved in all Drosophilids.
“Notably, the transcript of Drosophila CPT1 contains a predicted miR-33 binding site in its 3Ј UTR that is completely conserved in all Drosophilids (Fig. 7A).”
- Also stated in: § JOURNAL OF BIOLOGICAL CHEMISTRY 33657 · plain
“Interestingly, a conserved miR-33 binding site is present in the CPT1 transcript of all Drosophila species.”
Quote in the paperSubstantial claim - Also stated in: § JOURNAL OF BIOLOGICAL CHEMISTRY 33657 · plain
- Findingown data
The transcript lacking the predicted miR-33 binding site is expressed at very low concentrations in different human organs.
“Quantitative RT-PCR in different human organs, however, suggests that the transcript lacking the predicted miR-33 binding site is expressed at very low concentrations (supplemental Fig. S9B).”
Quote in the paperNot a substantial claim - Findingown data
miR-33 directly inhibits translation of the transcripts of several components of cellular β-oxidation.
“miR-33 directly inhibits translation of the transcripts of several components of cellular -oxidation.”
Quote in the paperSubstantial claim - Findingown data
Mutation of the seed region completely abolishes the reporter response.
“Mutation of the seed region completely abolishes this response”
Quote in the paperSubstantial claim - Findingown data
miR-33a is predicted to bind the 3' UTR of the human CROT transcript.
“C, predicted binding of miR-33a to the 3Ј UTR of the human CROT transcript.”
Quote in the paperSubstantial claim - Findingown data
Based on miRNA binding site prediction algorithms, binding sites for miR-33 in β-oxidation genes are absent in lower vertebrates.
“Surprisingly, based on miRNA binding site prediction algorithms, binding sites for miR-33 in -oxidation genes are absent in lower vertebrates.”
Quote in the paperNot a substantial claim - Findingnone given
No predicted miR-33 binding sites exist in the closest homolog of ABCA1 (CG1718).
“No predicted binding sites exist in the closest homolog of ABCA1 (CG1718).”
Quote in the paperNot a substantial claim - Findingown data
A similar effect of miR-33 on HADHB levels, albeit smaller, is observed in THP1 and Y1 cells.
“Of note, a similar effect on HADHB levels, albeit to a smaller extent, can be observed in THP1 cells and Y1 cells (Fig. 4A and supplemen- tal Fig. S5).”
Quote in the paperNot a substantial claim - Findingown data
In two cohorts of mice on a high fat diet, no increase in miR-33 levels was observed.
“In our two cohorts of mice on the high fat diet we did not observe an increase in miR-33 levels.”
Quote in the paperNot a substantial claim - Findingown data
Conserved targeting of the β-oxidation gene CPTI in the cholesterol auxotrophs Drosophila.
“Conserved targeting of the -oxidation gene CPTI in the cholesterol auxotrophs Drosophila.”
Quote in the paperSubstantial claim - Findingown data
SREBP2 transcript levels correlate well with miR-33a levels in most tissues and cell lines.
“Given the fact that SREBP2 transcript levels correlate well with miR-33a levels in most tissues and cell lines (data not shown), it seems likely that miR-33a in these diseases would be elevated as well.”
Quote in the paperNot a substantial claim - Interpretationown data
miR-33 reduces fatty acid degradation.
“thereby reducing fatty acid degradation”
Quote in the paperSubstantial claim - Interpretationreasoning
miR-33 cooperates with SREBP2 to maintain cellular lipid levels.
“miR-33 therefore cooperates with its embedding gene SREBP2 to maintain cellular lipid levels.”
Quote in the paperSubstantial claim - Interpretationown data
The regulation of β-oxidation by miR-33 could be evolutionarily conserved down to Drosophila melanogaster.
“We also supply data to suggest that the regulation of -oxidation could be evolutionarily conserved down to Drosophila melanogaster.”
Quote in the paperNot a substantial claim - Interpretationown data
miR-33 inhibits translation of transcripts encoding CPT1A, HADHB, and CROT.
“miR-33 also inhibits translation of several transcripts encoding proteins involved in fatty acid -oxidation including CPT1A, HADHB, and CROT, thereby reducing fatty acid degradation.”
Quote in the paperSubstantial claim - Interpretationown data
miR-33 inhibits translation of ABCA1.
“Taken together, our data suggest that endogenous miR-33 targets and represses translation of ABCA1, and reduces cellular cholesterol export.”
Quote in the paperSubstantial claim - Premiseown data
Three distinct proteins involved in fatty acid β-oxidation (HADHB, CPT1A, and CROT) are predicted targets for miR-33 in mammals and birds.
“Our attention was immediately drawn to fatty acid -oxidation, because three distinct proteins involved in this pathway are predicted targets for miR-33 in mammals and birds (HADHB, CPT1A, and CROT) (Fig. 5, A, C, and E, and supplemental Figs. S6 -S8 for evolutionary conservation).”
Quote in the paperSubstantial claim - Premisecitation
The ABCA1 mRNA contains putative miR-33a and miR-33b binding sites in its 3' UTR according to target prediction algorithms.
“According to several target gene prediction algorithms, the mRNA transcript of the cellular cholesterol export pump ABCA1 contains putative binding sites miR-33a and miR-33b in its 3Ј UTR (Pictar, Targetscan, Diana micro-T 3.0) (20 -23)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pictar, Targetscan, Diana micro-T 3.0
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
The influence of miR-33 on β-oxidation is of ancient origin.
“Taken together with conservation of the binding site in Drosophila CPT1, this reinforces the notion that the influence of miR-33 on -oxidation is of ancient origin.”
Quote in the paperNot a substantial claim - Interpretationreasoning
One genetic locus increases synthesis and limits export of cholesterol through two distinct mechanisms.
“one genetic locus increases synthesis and limits export of cholesterol through two distinct mechanisms”
Quote in the paperSubstantial claim - Interpretationreasoning
The selective pressure for the maintenance of a functional miR-33 binding site in fish CPT1 genes is less pronounced.
“It is therefore likely that the selective pressure for the maintenance of a functional miR-33 binding site in these genes is less pronounced.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Evolution has maintained the regulation by miR-33 of two enzymes that are sensitive to malonyl-CoA.
“In an elegant twist, evolution has maintained the regulation by miR-33 of two enzymes that are sensitive to malonyl-CoA by miR-33.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Increases in β-oxidation in situations of low malonyl-CoA levels might be limited by miR-33.
“Increases in -oxidation in situations of low malonyl-CoA levels might therefore be limited by miR-33.”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibition of fatty acid degradation by miR-33 is an elegant way to prevent degradation of newly synthesized lipids.
“Inhibition of fatty acid degradation by miR-33 therefore is an elegant way to prevent degradation of newly synthesized lipids (Fig. 8A).”
Quote in the paperSubstantial claim- Rests on an assumption: Activation of SREBPs stimulates transcription of several genes involved in fatty acid synthesis.
- Premisecitation
The CPT1 genes in fish have undergone additional duplications leading to a total of five CPT1 homologs.
“However, the CPT1 genes in fish have undergone additional duplications leading to a total of five CPT1 homologs (localized in Zebrafish chr25, 24637246 -24664477; chr24, 35296460 -35323563; chr3, 29494843-29531322; chr7, 49453562-49466880; and chr18, 9105052-9120233) (50).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Morash, 2010, Am. J. Physiol. Regul. Integr. Comp. Physiol. source
- Premisecitation
miR-33 shows tissue-dependent differences in 3' end length (isomirs) that might confound quantification by reverse transcription using hairpin primers.
“In these studies, we are relying on Northern blot analysis, because miR-33 shows tissue-dependent differences in 3Ј end length (Isomirs), which might confound quantification of miRNA lev- els by methods that rely on reverse transcription using hairpin primers (supplemental Fig. S13) (37,38).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [37] Benes, 2010, Methods source
- cites [38] Marti, 2010, Nucleic Acids Res.
Not checked in the free run.
- Interpretationown data
The conserved element in the Drosophila CPT1 3' UTR mediates the response to miR-33.
“suggesting that this element mediates the response to miR-33”
Quote in the paperSubstantial claim - Interpretationreasoning
Even small reductions of β-oxidation by miR-33 in a situation of hyperalimentation might contribute to an accumulation of lipids in the liver of patients with NAFLD or NASH.
“Even small reductions of -oxidation by miR-33 in a situation of hyperalimentation might contribute to an accumulation of lipids in the liver of patients with NAFLD or NASH.”
Quote in the paperSubstantial claim - Interpretationreasoning
miR-33a in NAFLD and NASH would be elevated as well.
“miR-33a in these diseases would be elevated as well”
Quote in the paperSubstantial claim - Interpretationreasoning
miR-33 cooperates with SREBPs to maintain cellular lipid levels.
“miR-33 cooperates with SREBPs to maintain cellular lipid levels.”
Quote in the paperSubstantial claim - Interpretationcitation
HADHA and HADHB levels limit capacity for β-oxidation in certain settings.
“These observations are consistent with the idea that HADHA and HADHB levels limit capacity for -oxidation in certain settings.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 32
- May combine two claims. 30
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSREBPs not only activate cholesterol synthesis but also fatty acid and phospholipid synthesis.
“However, SREBPs not only activate cholesterol synthesis but also fatty acid and phospholipid synthesis (2).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Horton, 2002, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigh levels of low density lipoprotein cholesterol are a major risk factor for the development of arteriosclerosis and death from cardiovascular causes.
“High levels of low density lipoprotein cholesterol are a major risk factor for the development of arteriosclerosis and death from cardiovascular causes (41).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [41] Nabel, 2003, N. Engl. J. Med. source
Classified as probably not a substantial claim.
PremisecitationGenes involved in cholesterol synthesis are coordinately up-regulated by the action of SREBP transcription factors.
“Genes involved in its synthesis are coordinately up-regulated by the action of SREBP transcription factors (2).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] Horton, 2002, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHomologs of SREBPs do not respond to changes in cholesterol, but rather changes in palmitate and/or phospholipids.
“It has been previously shown that the homologs of SREBPs do not respond to changes in cholesterol, but rather changes in palmitate and/or phospholipids (39,40).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [39] Dobrosotskaya, 2002, Science source
- cites [40] Seegmiller, 2002, Dev. Cell source
The Results report that palmitate reduced nuclear dSREBP in Drosophila S2 cells, whereas a cholesterol-containing sterol mixture failed to do so. The Discussion proposes that palmitic acid or a lipid derived from it regulates this pathway, but does not establish phospholipids as the signal. The claim also generalizes beyond the Drosophila homolog studied here. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCellular miR-33 levels are dependent on culture conditions and exogenous lipid supply.
“It has been previously noted that cellular miR-33 levels are dependent on culture conditions and exogenous lipid supply (36).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] Tsuchiya, 2009, Nucleic Acids Res. source
The Results (Screening of miRNAs related with differentiation; page unavailable) report that miR-33a increased in T84 cells between culture days 0 and 7, supporting a limited link between its level and culture conditions. The paper does not report that exogenous lipid supply affects miR-33 levels; its cell-culture methods describe serum-containing medium, not a lipid-supply comparison. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationABCA1-mediated cholesterol export is essential for the formation of HDL particles, because liver- and intestine-specific ABCA1 knockout mice show strong reductions in HDL levels.
“This process seems to be essential for the formation of HDL particles because liver-and intestine-specific knockout mice for ABCA1 show strong reductions in HDL levels (45)(46)(47).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [45] Brunham, 2009, Arterioscler. Thromb. Vasc. Biol. source
- cites [46] Singaraja, 2006, Arterioscler. Thromb. Vasc. Biol. source
The Abstract reports an 80% reduction in plasma HDL cholesterol in liver-specific ABCA1 knockout mice, supporting the liver-specific part of the claim. The paper does not report an intestine-specific knockout or its HDL levels. Its Discussion also says low HDL reflects increased catabolism as well as decreased synthesis, so the reduction alone does not establish a defect solely in particle formation. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [47] Brunham, 2006, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn reverse cholesterol transport, peripheral tissues export their excess cholesterol to HDL using the cholesterol export pumps ABCA1 and ABCG1.
“In a process termed reverse cholesterol transport, peripheral tissues export their excess cholesterol to HDL using the cholesterol export pumps ABCA1 and ABCG1 (44).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [44] Yvan-Charvet, 2007, J. Clin. Invest. source
The Introduction (page not provided) describes HDL-mediated cholesterol removal from peripheral tissues and identifies ABCA1 and ABCG1 as cholesterol-efflux transporters. It distinguishes their acceptors, however: ABCA1 exports to lipid-poor apoA-1, not mature HDL particles, whereas ABCG1 exports to HDL. Thus the claim is too broad in saying both pumps export cholesterol to HDL. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReduction of one subunit of the mitochondrial trifunctional protein in heterozygote knock-out mice leads to concomitant reduction of the other subunit.
“Previous studies have shown that reduction of one or the other component in heterozygote knock-out mice leads to a concomitant reduction of the other subunit (31)(32)(33).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [31] Ibdah, 2001, J. Clin. Invest. source
- cites [32] Ibdah, 2005, Gastroenterology source
The Assessment of the Temporal Relationship section (page unavailable) reports lower hepatic MTP α-subunit expression in α-heterozygous mice than in wild-type mice. The Background & Aims section says α-null homozygotes lack both subunits, but the paper does not show a concomitant reduction of the β-subunit in heterozygotes or examine β-heterozygous knockouts. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [33] Kao, 2006, Hum. Mol. Genet. source
The Discussion and Western blot and enzyme activity assay section report that both MTP subunits were reduced in affected mice with a mutation in the β-subunit. But the Identification of the mutated gene section identifies the affected mice as homozygous for a missense mutation, not heterozygous knockout mice; the paper therefore does not establish the claim for that genotype. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIncreased gene dosage of ABCA1 increases plasma HDL levels and protects from arteriosclerosis in animal models of hyperlipidemia.
“The reciprocal relationship also appears to be true in that increased gene dosage of ABCA1 increases plasma HDL levels and protects from arteriosclerosis in animal models of hyperlipidemia (48).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [48] Singaraja, 2001, J. Biol. Chem. source
The Results report significantly higher HDL-C in ABCA1 BAC transgenic mice than in control littermates, including when fed an atherogenic diet. The paper does not report an arteriosclerosis outcome or establish protection from arteriosclerosis in hyperlipidemic animal models; feeding an atherogenic diet does not by itself establish that protection. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationD. melanogaster is a cholesterol auxotroph and activation of SREBP is regulated by reduced levels of palmitate and/or phospholipids.
“D. melanogaster is a cholesterol auxotroph and activation of SREBP is regulated by reduced levels of palmitate and/or phospholipids.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [39] Dobrosotskaya, 2002, Science source
- cites [40] Seegmiller, 2002, Dev. Cell source
The paper says insects require dietary sterols, supporting the description of D. melanogaster as a cholesterol auxotroph. The Results and Discussion show that added palmitate inhibits dSREBP processing in cultured Drosophila cells, but the Discussion says it is not clear whether palmitate itself or a more complex lipid, possibly a phospholipid, is responsible. It does not establish that reduced phospholipid levels activate SREBP. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe mitochondrial trifunctional protein consists of an α subunit (HADHA) and a β subunit (HADHB).
“The mitochondrial trifunctional protein consists of an ␣ subunit (encoded by HADHA) and a  subunit (encoded by HADHB) (31).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [31] Ibdah, 2001, J. Clin. Invest. source
May combine two claims.
PremisecitationHepatic steatosis was observed both in mice carrying a hypomorphic allele of HADHB and in mice heterozygous for a null mutation of HADHA.
“This was observed both in mice that carry a hypomorphic allele of the HADHB gene and, notably, in mice heterozygote for a null mutation of the HADHA gene (encoding the ␣-subunit) (32,33).”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone givenLocalization and sequence of the miR-33 family is highly conserved down to insects and chordates, but not in worms.
“Localization and sequence of this miRNA family is highly conserved down to insects and chordates, but not in worms.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe 3' UTRs of CPT1A, CROT, and HADHB contain functional miR-33 binding sites.
“Cotransfection of these constructs with preMIR-33 significantly reduced activation of constructs containing the wild type 3Ј UTR when compared with transfection with a preMIR control (Fig. 5, B, D, and F).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown datamiR-33a and miR-33b differ only by two nucleotides outside the seed sequence.
“With regard to their sequence, miR-33a and miR-33b differ only by two nucleotides outside the seed sequence (Fig. 1B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMost species, including mouse, only possess miR-33a in the SREBP2 gene and have lost miR-33b from SREBP1.
“Most species (including the mouse), however, only possess miR-33a in the SREBP2 gene and have lost the sequence of miR-33b within the SREBP1 gene (Fig. 1A and supplemental Fig. S3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOverexpression of miR-33 sponges in HepG2 cells up-regulates ABCA1 protein and increases apoAI-dependent cholesterol export.
“overexpression of competitive antagonists of miR-33 action (i.e.miRNA sponges) in HepG2 cells led to an up-regulation of ABCA1 protein levels, which was accompanied by a significant increase in apoAI-dependent cellular cholesterol export (Fig. 3, C and D).”
Quote in the paperSubstantial claim- Rests on an assumption: The miRNA sponges and antagomirs specifically inhibit miR-33 without off-target effects.
May combine two claims.
FindingreasoningInhibition of miR-33 did not increase β-oxidation and HADHB levels.
“Several explanations seem possible to explain why we did not observe an increase in -oxidation and HADHB levels upon inhibition of miR-33.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-33 inhibits ABCA1 expression and consequentially cellular cholesterol export.
“The discovery that miR-33 inhibits ABCA1 expression and consequentially cellular cholesterol export suggests that one genetic locus increases synthesis and limits export of cholesterol through two distinct mechanisms (Fig. 8A).”
- Also stated in: § miR-33 in Cholesterol and Fatty Acid Metabolism · plain
“miR-33 reduces endogenous ABCA1 protein levels and modulates cellular cholesterol export in HepG2 cells.”
- Also stated in: § miR-33 in Cholesterol and Fatty Acid Metabolism · plain
“miR-33 reduces endogenous ABCA1 protein levels and modulates cellular cholesterol export in THP1 macrophages.”
Quote in the paperSubstantial claim- Also stated in: § miR-33 in Cholesterol and Fatty Acid Metabolism · plain
May combine two claims.
Findingown dataInhibition of miR-33 with miRNA sponges or antisense oligonucleotides does not cause a reproducible increase in fatty acid β-oxidation or alteration of HADHB and CPT1A protein levels in HepG2 cells.
“Inhibition of miR-33 with miRNA sponges or antisense oligonucleotides did not cause a reproducible increase in fatty acid -oxidation or alteration of HADHB and CPT1A protein levels in HepG2 cells (data not shown).”
Quote in the paperNot a substantial claim- Rests on an assumption: The miRNA sponges and antagomirs specifically inhibit miR-33 without off-target effects.
The quote only partly states this claim.
Findingown dataSite-directed mutagenesis of predicted seed binding sites in CPT1A, CROT, and HADHB 3' UTRs abolishes miR-33 responsiveness.
“Site-directed mutagenesis of one or two of the predicted seed binding sites completely abolished this response (mutated nucleotides indicated by asterisks).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCulturing cells at high density and/or in lipid-free medium leads to an increase of miR-33.
“Culturing cells at high density and/or in lipid-free medium leads to an increase of miR-33 (supplemental Fig. S12A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe two nucleotide changes in miR-33b lead to perfect complementarity with the CROT 3' UTR over 18 nucleotides, which could allow miR-33b to induce Ago2-dependent cleavage of the CROT transcript.
“Notably, these two changes lead to a perfect complementarity of miR-33b with the CROT 3Ј UTR over a total of 18 nucleotides, which could allow miR-33b to induce Ago2-dependent cleavage of the CROT transcript (supplemental Fig. S8, B versus C).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSeveral prediction algorithms do not recognize CPT1A as a miR-33 target gene because they use a short 3' UTR generated from an alternative exon.
“It should be noted that several prediction algorithms do not recognize CPT1A as a miR-33 target gene.This is due to the fact that these algorithms utilize a short 3Ј UTR generated from an alternative exon (supplemen- tal Fig. S9A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOverexpression of miR-33 increases cellular free fatty acid levels and triacylglycerides.
“When analyzing cellular extracts by TLC we observed a significant increase in cellular free fatty acid levels and triacylglycerides (Fig. 6D and supplemental Fig. S11).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-33 reduces endogenous ABCA1 protein levels and modulates cellular cholesterol export in HepG2 cells.
“miR-33 reduces endogenous ABCA1 protein levels and modulates cellular cholesterol export in HepG2 cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-33 reduces endogenous ABCA1 protein levels and modulates cellular cholesterol export in THP1 macrophages.
“miR-33 reduces endogenous ABCA1 protein levels and modulates cellular cholesterol export in THP1 macrophages.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datamiR-33a localization within SREBP2 and sequences are evolutionary conserved.
“miR-33a localization within SREBP2 and sequences are evolutionary conserved.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere was a small, but not significant, trend for reduced miR-33 levels.
“In fact, there was a small, but not significant, trend for reduced miR-33 levels, as one might intuitively expect in a situation of hyperalimentation.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown datamiR-33 reduces β-oxidation and alters cellular fatty acid metabolism.
“miR-33 reduces -oxidation and alters cellular fatty acid metabolism.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCPT1A is the liver-specific isoform of the enzyme that converts acyl-CoA to acylcarnitine and allows fatty acids to enter the mitochondrion for β-oxidation.
“CPT1A is the liver-specific isoform of the enzyme that converts acyl-CoA to acylcarnitine and thereby allows fatty acids to enter the mitochondrion where fatty acid -oxidation takes place (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Bonnefont, 2004, Mol. Aspects Med. source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationABCA1 acts as a cellular cholesterol export pump and has the unique capability to export cholesterol to lipid-free apoAI, involved in HDL particle formation and reverse cholesterol transport.
“ABCA1 acts as a cellular cholesterol export pump.Although there are a number of cholesterol efflux pumps, ABCA1 has the unique capability to export cholesterol to lipid-free apolipoprotein AI (apoAI) and is therefore involved in the initial step of high-density lipoprotein particle formation in liver, as well as reverse cholesterol transport (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Tall, 2008, Cell Metab. source
May combine two claims.
InterpretationreasoningThe genetic locus encoding SREBP2 and miR-33 contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly synthesized lipids.
“The genetic locus encoding SREBP2 and miR-33 therefore contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly synthesized lipids.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCROT is a peroxisomal enzyme that couples short chain fatty acids to carnitine and allows their entry into the mitochondrial matrix.
“CROT, sometimes abbreviated COT, is a peroxisomal enzyme that couples short chain fatty acids to carnitine and thereby allows their entry in the mitochondrial matrix.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Wanders, 2010, Biochim. Biophys. Acta source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCPT1A activity is rate-limiting for β-oxidation and is the most highly regulated element in this metabolic pathway.
“Although not strictly an enzyme of the -oxidation, the activity of CPT1A is rate-limiting for oxidation, and is the most highly regulated element in this metabolic pathway (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Saggerson, 2008, Annu. Rev. Nutr. source
May combine two claims.
Interpretationown dataEndogenous miR-33 targets and represses translation of ABCA1 and reduces cellular cholesterol export.
“Taken together, our data suggest that endogenous miR-33 targets and represses translation of ABCA1, and reduces cellular cholesterol export.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationCancer cell lines and proliferative cells often express transcripts with shorter 3' UTRs.
“It has recently been noted that cancer cell lines and proliferative cells often express transcripts with shorter 3Ј UTRs (51).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Sandberg, 2008, Science source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationLoss-of-function alleles of ABCA1 are associated with a decrease in HDL levels and might be associated with an increase in cardiovascular mortality.
“Loss-of-function alleles of ABCA1 are associated with a decrease in HDL levels and might be associated with an increase in cardiovascular mortality (42,49).”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
InterpretationreasoningIncreasing ABCA1 protein levels by inhibiting miR-33 might prove useful in the prevention of cardiovascular diseases.
“Given its preventive effect in mice, increasing ABCA1 protein levels by inhibiting miR-33 might therefore prove useful in the prevention of cardiovascular diseases.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInactivating mutations in ABCA1 lead to the development of Tangier disease, characterized by absence of HDL and accumulation of cholesterol in peripheral tissues.
“Inactivating mutations in ABCA1 lead to the development of Tangier disease, which is characterized by the absence of HDL and the accumulation of cholesterol in peripheral tissues (42).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Brunham, 2008, JAMA source
May combine two claims.
PremisecitationCROT is localized to the peroxisomes, it serves to transfer remnants from peroxisomal β-oxidation to the mitochondria and therefore fuels mitochondria with fatty acids independently of CPT1A.
“Although CROT is localized to the peroxisomes, it serves to transfer remnants from peroxisomal -oxidation to the mitochondria and therefore fuels mitochondria with fatty acids independently of CPT1A (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Wanders, 2010, Biochim. Biophys. Acta source
May combine two claims.
InterpretationreasoningWhen decreases in cellular cholesterol levels trigger the activation of SREBP transcription factors, the presence of miR-33 prevents cholesterol from leaving the cell by suppressing expression of ABCA1, thus allowing cellular cholesterol levels to be restored.
“When decreases in cellular cholesterol levels trigger the activation of SREBP transcription factors, the presence of miR-33 prevents cholesterol from leaving the cell by suppressing expression of ABCA1, thus allowing cellular cholesterol levels to be restored (Fig. 8A).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElevated levels of high density lipoprotein cholesterol reduce the risk of arteriosclerosis.
“On the other hand, elevated levels of high density lipoprotein cholesterol reduces the risk of arteriosclerosis (42,43).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHADHB encodes the β-subunit of the mitochondrial trifunctional protein that carries out the last three steps of β-oxidation.
“The gene HADHB encodes for the -subunit of the mitochondrial trifunctional protein that carries out the last three steps of -oxidation (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Eaton, 2000, Biochem. Soc. Trans. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPeroxisomal β-oxidation is limited to degradation of long- and medium-chain fatty acids and cannot oxidize short chain fatty acids.
“Peroxisomal -oxidation is limited to the degradation of long-and medium-chain fatty acids as it is not able to oxidize short chain fatty acids (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Wanders, 2010, Biochim. Biophys. Acta source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningAgents that alter HDL cholesterol levels carry the potential to reduce cardiovascular diseases.
“Agents that alter HDL cholesterol levels therefore carry the potential to reduce cardiovascular diseases.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNAFLD is by far the most common liver ailment.
“Presently, non-alcoholic fatty liver disease (NAFLD) is by far the most common liver ailment (53).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Angulo, 2002, N. Engl. J. Med. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningAltering the levels of HADHB might change the potential maximum flux through β-oxidation, but might have little influence under most conditions where fatty acid supply in the mitochondria is rate-limiting for β-oxidation.
“Likewise, altering the levels of HADHB might change the potential maximum flux through -oxidation, but might have little influence under most conditions where fatty acid supply in the mitochondria is rate-limiting for -oxidation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningProtein amounts of SREBPs represent the maximum potential to respond to changes in lipid levels.
“Protein amounts of SREBPs therefore represent the maximum potential to respond to changes in lipid levels.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningInterfering with miR-33 function in vivo holds promise in increasing HDL cholesterol levels and may also prove beneficial for treatment of NAFLD and NASH.
“Interfering with miR-33 function in vivo therefore not only holds promise in increasing HDL cholesterol levels but may also prove beneficial for treatment of NAFLD and NASH.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNAFLD affects 10-25% of the general population and up to 75% of obese type II diabetic patients.
“With the increasing prevalence of obesity, it affects 10 -25% of the general population and up to 75% of obese type II diabetic patients (54).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] Marchesini, 2008, J. Clin. Endocrinol. Metab. source
May combine two claims.
PremisecitationSREBP2 transcript levels in NAFLD and NASH are elevated 3- and 7-fold, respectively.
“A recent study of Cabellero and co-workers (55) suggests that SREBP2 transcript levels in NAFLD and NASH are elevated 3-and 7-fold, respectively.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Caballero, 2009, J. Hepatol. source
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningReduced HADHB concentrations might help maintain adequate intermediary product levels in a situation where the enzyme that supplies the substrates for β-oxidation (CPT1A and CROT) is inhibited.
“The relevance of targeting HADHB is not quite as apparent, although reduced HADHB concentrations might help maintain adequate intermediary product levels in a situation where the enzyme that supplies the substrates for -oxidation (CPT1A and CROT) is inhibited.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The 500-bp genomic region surrounding miR-33a used in lentiviral vectors specifically expresses miR-33a without affecting other genes or small RNAs.
“we transduced HepG2 cells with a lentiviral expression vector constitutively driving expression of a 500-bp genomic region surrounding the miR-33a sequence.”
The paper relies on this without support.
The antibodies used for Western blot analysis specifically detect their intended targets (ABCA1, HADHB, CPT1A, HADHA, GAPDH, and β-actin).
“Antibodies were used at the following dilutions: ABCA1 at 1:1,000 (AB.H10, Santa Cruz Biotechnologies), HADHB at 1:1,000 (ARP48133, Aviva Systems Biology, San Diego, CA), HADHA at 1:1,000 (HPA015536, Sigma), CPT1 1:1000 (Proteintech, Manchester, UK), GAPDH at 1:2,000 (6C5, Pierce-ThermoFisher), and -actin at 1:10,000 (AC-40, Sigma).”
The paper relies on this without support.
The miRNA sponges and antagomirs specifically inhibit miR-33 without off-target effects.
“miR-33 antagomir denotes a 1:1 mixture of miR-33a and miR-33b antagomir.”
The paper relies on this without support.
D. melanogaster and other Drosophilids are cholesterol auxotrophs (cannot synthesize cholesterol).
“Notably, miR-33 is highly conserved in D. melanogaster (and other Drosophilids), which are auxotrophs for cholesterol, i.e. they cannot synthesize cholesterol.”
The paper relies on this without support.
SREBPs of higher organisms help to coordinately induce genes involved in cholesterol, fatty acid, and phospholipid synthesis.
“As mentioned above, SREBPs of higher organisms help to coordinately induce genes involved in cholesterol, fatty acid, and phospholipid synthesis.”
The paper relies on this without support.
Activation of SREBPs stimulates transcription of several genes involved in fatty acid synthesis.
“Activation of SREBPs stimulates transcription of several genes involved in fatty acid synthesis.”
The paper relies on this without support.
CPT1A is the rate-limiting and most highly regulated step in β-oxidation.
“As mentioned before, CPT1A is the rate-limiting and most highly regulated step in -oxidation.”
The paper relies on this without support.
CROT and CPT1A are enzymes that couple fatty acids to carnitine.
“CROT and CPT1A are enzymes that couple fatty acids to carnitine.”
The paper relies on this without support.
The protein product of the HADHB transcript forms the β-subunit of the mitochondrial trifunctional protein, which carries out three steps of β-oxidation.
“The protein product of the HADHB transcript forms the -subunit of the mitochondrial trifunctional protein, which carries out three steps of -oxidation.”
The paper relies on this without support.
No single mouse model or feeding regimen reliably reproduces the features of NAFLD and NASH.
“Unfortunately, no single mouse model or feeding regimen reliably reproduces the features of NAFLD and NASH.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
miR-33a and miR-33b help prevent further loss of lipids by targeting genes involved in cholesterol trafficking and efflux and fatty acid β-oxidation.
“miR-33a and miR-33b help prevent further loss of lipids by targeting genes involved in cholesterol trafficking and efflux”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Gerin et al., 2010
The Discussion says miR-33 suppresses ABCA1 to prevent cholesterol from leaving cells, and the results show that miR-33a reduces cholesterol export and targets genes involved in fatty acid β-oxidation. The paper also identifies a predicted cholesterol-distribution target, NPC1. However, it says the experiments focused on miR-33a; shared predicted targets and a mixed miR-33a/miR-33b antagomir experiment do not establish the full effect for miR-33b separately. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn miR-33a knockout mice or when miR-33a is suppressed by synthetic nucleic acids such as antagomirs, the expression of ABCA1 in macrophages and the liver is increased.
“In miR-33a knockout mice or when miR-33a is suppressed by synthetic nucleic acids such as antagomirs, the expression of ABCA1 in macrophages and the liver is increased 11 - 15) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [15]
In “miR-33 in Cholesterol and Fatty Acid Metabolism” (p. 33655), the paper reports increased ABCA1 protein after miR-33 inhibition with sponges in HepG2 liver-derived cells; it also tests antagomirs in those cells. It does not report miR-33a knockout mice or show increased ABCA1 after suppression in mouse liver or macrophages. Its macrophage experiment instead tests miR-33a overexpression. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTwo miR-33 genes are present in humans: miR-33b in intron 17 of Srebp-1 on chromosome 17, and miR-33a in intron 16 of Srebp-2 on chromosome 22.
“Two miR-33 genes are present in humans: miR-33b, which is present in intron 17 of the Srebp-1 gene on chromosome 17, and miR-33a, which is located in intron 16 of the Srebp-2 gene on chromosome 22.”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [11]
The section “miR-33a Is Produced from an Intron of the SREBP2 Gene” states that human miR-33a and miR-33b lie in introns of SREBP2 and SREBP1, respectively. Our copy does not give the claimed intron numbers or chromosome numbers, so those details are not supported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn mice, there is only one miR-33 gene, conserved with human miR-33a and located within intron 15 of the mouse Srebp-2 gene.
“In mice, however, there is only one miR-33 gene, which is conserved with human miR-33a and located within intron 15 of the mouse Srebp-2 gene.”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [11]
The section “miR-33a Is Produced from an Intron of the SREBP2 Gene” says that mice possess miR-33a in SREBP2 but lack miR-33b, and describes miR-33a as highly conserved. It does not specify that the mouse sequence is in intron 15, so that part of the claim is unsupported by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe most well-known target gene of miR-33a/b is ABCA1.
“The most well-known target gene of miR-33a/b is ATP-binding cassette subfamily A member 1 (ABCA1).”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [15]
miR-33 suppresses genes involved in mitochondrial β-oxidation, such as CPT1A, HADHB, and CROT.
“MiR-33 suppresses genes involved in mitochondrial β-oxidation, such as carnitine palmitoyltransferase 1A (CPT1A), hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit b (HADHB), and carnitine O-octanoyltransferase (CROT) 15 , 17 , 34 , 35) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [15]
miR-33 is a highly conserved miRNA family within the intronic sequences of the Srebp genes in organisms ranging from Drosophila to humans.
“We and others provided identification of a highly conserved miRNA family, miR-33, within the intronic sequences of the Srebp genes in organisms ranging from Drosophila to humans (11–14).”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [11]
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.
Two articles are cited with a three-reference range
MinorThe addendum says two articles were presented online but cites references 56-58, a range containing three separately listed articles.
“two articles were presented online describing the effect of miR-33 on ABCA1 and cholesterol metabolism (56 -58).”
“58. Marquart, T. J., Allen, R. M., Ory, D. S., and Balda ´n, A. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 12228 -12232”
Cholesterol-export error bars are described as both SD and SE
MinorThe cholesterol-export methods say the displayed values are means ± SD, whereas the Figure 3 legend describes the cholesterol-export results as means ± SE. These are different measures of variability.
“Experiments were performed using 5 to 8 replicates per experimental condition and values shown represent mean Ϯ S.D.”
“Values represent mean Ϯ S.E. of 6 replicates.”
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Genome duplication events have led to a diversification in the CPT I gene family in fish
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Malonyl-CoA inhibition of peroxisomal carnitine octanoyltransferase
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Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer
Snaebjornsson, M. T., Janaki-Raman, S., & Schulze, A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.010 · Cited by 1,097 · see citing works
MicroRNAs in metabolism and metabolic disorders
Rottiers, V., & Näär, A. M. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3313 · Cited by 1,156 · see citing works
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling
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., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102281108 · Cited by 670 · see citing works
“(11) reported similar effects of miR-33 on CROT, CPT1a, and HADHB expression.”
BackgroundInhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Rayner, K. J., Esau, C. C., Hussain, F. N., McDaniel, A. L., Marshall, S. M., van Gils, J. M., Ray, T. D., Sheedy, F. J., Goedeke, L., Liu, X., et al. (2011) · Nature · doi:10.1038/nature10486 · Cited by 706 · see citing works
Rayner, K. J., Sheedy, F. J., Esau, C. C., Hussain, F. N., Temel, R. E., Parathath, S., van Gils, J. M., Rayner, A. J., Chang, A. N., Suarez, Y., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57275 · Cited by 690 · see citing works
MicroRNA Regulation of Atherosclerosis
Feinberg, M. W., & Moore, K. J. (2016) · Circulation Research · doi:10.1161/circresaha.115.306300 · Cited by 630 · see citing works
“Thus, transcription of SREBF2 and SREBF1 also results in expression of miR-33a and b, which cooperate with their host genes to balance cellular lipid levels by repressing genes that oppose SREBP-regulated pathways, such those involved in cholesterol efflux (ABCA1 and ABCG1) and fatty acid oxidation (hydroxyacyl-CoA de…”
BackgroundBarrett, L. W., Fletcher, S., & Wilton, S. D. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-0990-9 · Cited by 603 · see citing works
“end of the miRNA, which then recruits Argonaut and inhibits translation of the mRNA (see [62, 137, 166].”
BackgroundDevelopment of microRNA therapeutics is coming of age
van Rooij, E., & Kauppinen, S. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201100899 · Cited by 625 · see citing works
Inhibition of microRNA function by antimiR oligonucleotides
Stenvang, J., Petri, A., Lindow, M., Obad, S., & Kauppinen, S. (2012) · Silence · doi:10.1186/1758-907x-3-1 · Cited by 556 · see citing works
“In 2010, a number of independent studies reported that miR-33a, which is embedded within an intron of the sterol regulatory element-binding protein-2 (SREBP2) gene, targets the ATP-binding cassette transporter A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transp…”
BackgroundSREBPs: metabolic integrators in physiology and metabolism
Jeon, T.-I., & Osborne, T. F. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.10.004 · Cited by 513 · see citing works
“miR-33’s have also been shown to regulate fatty acid oxidation and glucose metabolism indicating that these micro RNAs may have a broader role in regulating metabolism(15, 16).”
BackgroundIncreased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance
Choi, S. H., & Ginsberg, H. N. (2011) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.04.007 · Cited by 418 · see citing works
“In contrast, miR-33, which is transcribed from an SREBP2 intron, inhibits transcription of several genes involved in FA oxidation as well as the gene for cholesterol transporter, ABCA1 (66).”
BackgroundCholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis
Musso, G., Gambino, R., & Cassader, M. (2012) · Progress in Lipid Research · doi:10.1016/j.plipres.2012.11.002 · Cited by 410 · see citing works
Ouimet, M., Ediriweera, H. N., Gundra, U. M., Sheedy, F. J., Ramkhelawon, B., Hutchison, S. B., Rinehold, K., van Solingen, C., Fullerton, M. D., Cecchini, K., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81676 · Cited by 394 · see citing works
MicroRNA-mediated regulation of glucose and lipid metabolism
Agbu, P., & Carthew, R. W. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00354-w · Cited by 368 · see citing works
Malekmohammad, K., Bezsonov, E. E., & Rafieian‐Kopaei, M. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.707529 · Cited by 353 · see citing works
Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP
Xu, X., So, J.-S., Park, J.-G., & Lee, A.-H. (2013) · Seminars in liver disease (Print) · doi:10.1055/s-0033-1358523 · Cited by 299 · see citing works
Fernandez-Hernando, C. F., Suárez, Y., Rayner, K. J., & Moore, K. J. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283428d9d · Cited by 307 · see citing works
MicroRNAs in Metabolic Disease
Fernández-Hernando, C., Ramírez, C. M., Goedeke, L., & Suárez, Y. (2013) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.112.300144 · Cited by 257 · see citing works
Recent advances in physiological lipoprotein metabolism
Ramasamy, I. (2013) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2013-0358 · Cited by 234 · see citing works
Regulation of cholesterol homeostasis
Goedeke, L., & Fernández-Hernando, C. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0857-5 · Cited by 309 · see citing works
“In addition to the cholesterol transport genes, ABCA1, ABCG1 and NPC1, two independent studies have recently shown that miR-33a and -b binding sites are highly conserved in the 30UTR of genes involved in fatty acid oxidation including, Cpt1a, Crot, Hadhb, and Ampk [16].”
BackgroundmicroRNA-33 regulates macrophage autophagy in atherosclerosis
Ouimet, M., Ediriweera, H., Afonso, M. S., Ramkhelawon, B., Singaravelu, R., Liao, X., Bandler, R. C., Rahman, K., Fisher, E. A., Rayner, K. J., et al. (2017) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.308916 · Cited by 221 · see citing works
Zhu, Y., Yang, L., Zhang, Q., Liu, J., Li, T.-J., Yang, J., Zeng, C., & Zhuang, S. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1278 · Cited by 210 · see citing works
Roles of microRNA on cancer cell metabolism
Chen, B., Li, H., Zeng, X., Yang, P., Liu, X., Zhao, X., & Liang, S. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-228 · Cited by 205 · see citing works
Gao, W. Q., He, H., Wang, Z., Zhao, H., Lian, X., Wang, Y., Zhu, J., Yan, J., Zhang, D., Yang, Z., et al. (2012) · Lipids in Health and Disease · doi:10.1186/1476-511x-11-55 · Cited by 198 · see citing works
DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels
Pfeiffer, L., Wahl, S., Pilling, L. C., Reischl, E., Sandling, J. K., Kunze, S., Holdt, L. M., Kretschmer, A., Schramm, K., Adamski, J., et al. (2015) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.114.000804 · Cited by 194 · see citing works
Metabolic and functional relevance of HDL subspecies
Asztalos, B. F., Tani, M., & Schaefer, E. J. (2011) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283468061 · Cited by 192 · see citing works
Karunakaran, D., Thrush, A. B., Nguyen, M.-A., Richards, L., Geoffrion, M., Singaravelu, R., Ramphos, E., Shangari, P., Ouimet, M., Pezacki, J. P., et al. (2015) · Circulation Research · doi:10.1161/circresaha.117.305624 · Cited by 188 · see citing works
Mir-33 regulates cell proliferation and cell cycle progression
Cirera-Salinas, D., Pauta, M., Allen, R. M., Salerno, A., Ramírez, C., Chamorro-Jorganes, A., Wanschel, A., Lasunción, M. A., Morales-Ruiz, M., Suárez, Y., et al. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19421 · Cited by 177 · see citing works
“miR33a and miR-33b are co-transcribed with its host genes, like many intronic miRNAs, and they target genes involved in regulating cholesterol homeostasis (Abca1, Abcg1 and Npc1)(20-22) and fatty acid metabolism (Ampk, Cpt1a, Crot, Hadhb and Sirt6 ).(23,24) These findings suggest that Srebp genomic loci, which encode…”
BackgroundRotllan, N., Ramírez, C. M., Aryal, B., Esau, C. C., & Fernández-Hernando, C. (2013) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.113.301732 · Cited by 174 · see citing works
MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR
Vallim, T. Q. D. A., Tarling, E., Kim, T., Civelek, M., Baldán, Á., Esau, C. C., & Edwards, P. (2013) · Circulation Research · doi:10.1161/circresaha.112.300648 · Cited by 142 · see citing works
Recent Highlights of ATVB Atherosclerosis
Lu, H. S., & Daugherty, A. (2015) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.305380 · Cited by 76 · see citing works
Allen, R. M., Marquart, T. J., Albert, C. J., Suchy, F. J., Wang, D. Q. ‐., Ananthanarayanan, M., Ford, D. A., & Baldán, Á. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201201228 · Cited by 159 · see citing works
“We (Marquart et al, 2010) and others (Gerin et al, 2010; Horie et al, 2010; Najafi-Shoushtari et al, 2010; Rayner et al, 2010) recently showed that the evolutionarily conserved miR-33 is expressed from within intron 16 of SREBP-2 , and that this miRNA downregulates the expression of the sterol…”
Regulation of cholesterol and bile acid homeostasis by the CYP7A1/SREBP2/miR-33a axis
Li, T.-G., Francl, J., Boehme, S., & Chiang, J. Y. L. (2013) · Hepatology · doi:10.1002/hep.26427 · Cited by 153 · see citing works
“miR-33a, encoded by intron 16 of the SREBP2 gene, has recently been shown to regulate cellular cholesterol homeostasis,(9) biliary bile acid secretion,(10) and fatty acid oxidation.(11) Additionally, when cellular cholesterol levels decrease, miR-33a expression is coinduced with SREBP2 mRNA.”
BackgroundNguyen, M.-A., Wyatt, H., Susser, L., Geoffrion, M., Rasheed, A., Duchez, A., Cottee, M. L., Afolayan, E., Farah, E., Kahiel, Z., et al. (2019) · ACS Nano · doi:10.1021/acsnano.8b09679 · Cited by 157 · see citing works
MicroRNA 33 Regulates Glucose Metabolism
Ramírez, C. M., Goedeke, L., Rotllan, N., Yoon, J.-H., Cirera-Salinas, D., Mattison, J. A., Suárez, Y., de Cabo, R., Gorospe, M., & Fernández-Hernando, C. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00016-13 · Cited by 154 · see citing works
The Role of MicroRNAs in Cholesterol Efflux and Hepatic Lipid Metabolism
Moore, K. J., Rayner, K. J., Suárez, Y., & Fernandez-Hernando, C. F. (2011) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-081810-160756 · Cited by 152 · see citing works
“Indeed, they demonstrated that overexpression of miR-33a reduced cellular fatty acid β-oxidation (30).”
Galicia-Garcia, U., Jebari, S., Larrea-Sebal, A., Uribe, K., Siddiqi, H., Ostolaza, H., Benito-Vicente, A., & Martín, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134725 · Cited by 141 · see citing works
Goedeke, L., Salerno, A., Ramírez, C. M., Guo, L., Allen, R. M., Yin, X., Langley, S. R., Esau, C., Wanschel, A., Fisher, E. A., et al. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404046 · Cited by 145 · see citing works
“In addition to the effect of miR-33 in controlling cholesterol efflux and HDL-C synthesis, miR-33 also regulates the expression of genes involved in fatty acid oxidation and insulin signaling, including CROT , CPT1A , HADHB , AMPK, and IRS2 (Gerin et al , 2010; Davalos et al , 2011).”
Macrophage metabolism in atherosclerosis
Bories, G. F. P., & Leitinger, N. (2017) · FEBS Letters · doi:10.1002/1873-3468.12786 · Cited by 145 · see citing works
New insights into the mechanism of low high-density lipoprotein cholesterol in obesity
Wang, H., & Peng, D.-Q. (2011) · Lipids in Health and Disease · doi:10.1186/1476-511x-10-176 · Cited by 140 · see citing works
“subunit of the mitochondrial trifunctional protein) [88].”
MicroRNAs: Emerging roles in adipogenesis and obesity
Peng, Y., Yu, S., Li, H., Xiang, H., Peng, J., & Jiang, S. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.05.006 · Cited by 139 · see citing works
A Regulatory Role for MicroRNA 33* in Controlling Lipid Metabolism Gene Expression
Goedeke, L., Vales-Lara, F. M., Fenstermaker, M., Cirera-Salinas, D., Chamorro-Jorganes, A., Ramírez, C. M., Mattison, J. A., de Cabo, R., Suárez, Y., & Fernández-Hernando, C. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01714-12 · Cited by 140 · see citing works
“works to reduce cellular fatty acid oxidation by targeting carnitine O-octanoyltransferase (CROT), carnitine palmitoyltransferase 1A (CPT1a), hydroxyacyl coenzyme A (hydroxyacyl-CoA) dehydrogenase subunit beta (HADHB), and AMP kinase subunit alpha (AMPK ), as well as insulin signaling, by targeting insulin receptor su…”
BackgroundInfluentialTakeshita, Y., Takamura, T., Honda, M., Kita, Y., Zen, Y., Kato, K., Misu, H., Ota, T., Nakamura, M., Yamada, K., et al. (2014) · Diabetologia · doi:10.1007/s00125-013-3149-9 · Cited by 136 · see citing works
“Upregulation of SREBF2 potentially represses the expression of hepatocyte nuclear factor 4, which is required for CPT1 transcription [35].”
BackgroundSREBP: a novel therapeutic target
Xu, X., & Song, B. (2012) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gms112 · Cited by 134 · see citing works
Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis
Price, N. L., Rotllan, N., Canfrán-Duque, A., Zhang, X., Pati, P., Arias, N., Moen, J., Mayr, M., Ford, D. A., Baldán, Á., et al. (2017) · Cell reports · doi:10.1016/j.celrep.2017.10.023 · Cited by 129 · see citing works
“[HADHB]) (Dávalos et al., 2011; Gerin et al., 2010).”
Wijesekara, N., Zhang, L.-H., Kang, M. H., Abraham, T., Bhattacharjee, A., Warnock, G., Verchere, C., & Hayden, M. (2012) · Diabetes · doi:10.2337/db11-0944 · Cited by 141 · see citing works
MicroRNAs as Potential Biomarkers in Atherosclerosis
Churov, A. V., Summerhill, V. I., Grechko, A. V., Orekhova, V. A., & Orekhov, A. N. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225547 · Cited by 124 · see citing works
“The studies showed that overexpression of miR-33 strongly inhibited expression of ATP-binding cassette transporter (ABCA1) at the RNA and protein level and reduced cellular cholesterol efflux to apolipoprotein A-I (ApoA-I), an important step in regulating reverse cholesterol transport [122,123].”
BackgroundMicroRNAs in metabolism and metabolic diseasesPreprint
Rottiers, V., Najafi-Shoushtari, S. H., Kristo, F., Gurumurthy, S., Zhong, L., Li, Y.-X., Cohen, D. E., Gerszten, R. E., Bardeesy, N., Mostoslavsky, R., et al. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011049 · Cited by 130 · see citing works
“In accord with miR-33 regulation of fatty acid b-oxidation genes, excess miR-33 resulted in increased intracellular triglyceride and fatty acid levels as well as increased lipid droplet formation in human hepatoma cells and in the Drosophila fat body (Gerin et al. 2010; Davalos et al. 2011).”
InfluentialNutraceuticals and Functional Foods in the Management of Hyperlipidemia
Chen, G., Wang, H., Zhang, X., & Yang, S. (2013) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2011.629354 · Cited by 120 · see citing works
“…shown that miR-33a (microRNA-33a), embedded within intron of SREBP- 2 gene, collaborates with SREBP host genes to control cholesterol homeostasis (Gerin et al., 2010; Horie et al., 2010; Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010). miR-33a targets in mRNA of…”
BackgroundInfluentialRottiers, V., Obad, S., Petri, A., McGarrah, R., Lindholm, M. W., Black, J. C., Sinha, S., Goody, R. J., Lawrence, M. S., deLemos, A. S., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006840 · Cited by 121 · see citing works
Jeon, T.-I., Esquejo, R. M., Roqueta‐Rivera, M., Phelan, P. E., Moon, Y.-A., Govindarajan, S. S., Esau, C., & Osborne, T. F. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.010 · Cited by 118 · see citing works
“Recent studies have uncovered a pair of miRNAs, miR-33a and miR-33b, that are encoded within introns of the human SREBF-2 and SREBF-1 genes, respectively (Gerin et al., 2010; Horie et al., 2010; Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
BackgroundJun, S., Datta, S., Wang, L., Pegany, R. B., Cano, M., & Handa, J. T. (2018) · Experimental Eye Research · doi:10.1016/j.exer.2018.09.023 · Cited by 115 · see citing works
Marquart, T. J., Wu, J., Lusis, A. J., & Baldán, Á. (2013) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.112.300639 · Cited by 110 · see citing works
Price, N. L., Singh, A. K., Rotllan, N., Goedeke, L., Wing, A., Canfrán-Duque, A., Diaz-Ruiz, A., Araldi, E., Baldán, Á., Camporez, J.-P., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.074 · Cited by 110 · see citing works
“…found to target genes involved in a number of other important metabolic functions including fatty acid metabolism (CPT1, CROT, HADHb), insulin signaling (IRS2), and mitochondrial function (AMPK, PGC1a) (Dávalos et al., 2011; Gerin et al., 2010; Karunakaran et al., 2015; Ouimet et al., 2015, 2017).”
Mechanistic Role of MicroRNAs in Coupling Lipid Metabolism and Atherosclerosis
Novák, J., Olejníčková, V., Tkáčová, N., & Santulli, G. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-22380-3_5 · Cited by 109 · see citing works
MicroRNA 302a is a novel modulator of cholesterol homeostasis and atherosclerosis
Meiler, S., Baumer, Y., Toulmin, E., Seng, K., & Boisvert, W. (2014) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.304878 · Cited by 110 · see citing works
Kerr, T. A., Korenblat, K., & Davidson, N. O. (2011) · Translational research · doi:10.1016/j.trsl.2011.01.008 · Cited by 104 · see citing works
“The functional consequences of miR-33 expression include decreased expression of the cholesterol export pump, ABCA1 [26,27,29] and in addition decreased expression of genes involved in fatty acid oxidation [28].”
BackgroundPhu, T. A., Ng, M., Vu, N. K., Bouchareychas, L., & Raffaı̈, R. L. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.03.008 · Cited by 104 · see citing works
MiR-103 Controls Milk Fat Accumulation in Goat (Capra hircus) Mammary Gland during Lactation
Lin, X., Luo, J., Zhang, L., Wang, W., & Gou, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079258 · Cited by 101 · see citing works
“Previous studies have shown that some sense oriented intronic miRNAs are co-regulated with their host genes; these miRNAs can positively assist the function of their co-regulated host genes [51,52].”
BackgroundInfluentialGambari, R., Fabbri, E., Borgatti, M., Lampronti, I., Finotti, A., Brognara, E., Bianchi, N., Manicardi, A., Marchelli, R., & Corradini, R. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.08.007 · Cited by 101 · see citing works
microRNAs in the onset and development of cardiovascular disease
Vickers, K. C., Rye, K., & Tabet, F. (2013) · Clinical Science · doi:10.1042/cs20130203 · Cited by 101 · see citing works
“miR-33a/b was also found to play a key role in fatty acid β-oxidation by directly targeting CROT (carnitine O-octanyl transferase), CPT1A (carnitine palmitoyltransferase 1A) and HADHB (hydroxyacyl-CoA dehydrogenase-3-ketoacyl-CoA thiolase-enoyl-CoA hydratase β-subunit) [38,46].”
BackgroundInterplay of mitochondrial metabolism and microRNAs
Geiger, J., & Dalgaard, L. T. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2342-7 · Cited by 101 · see citing works
Pachikian, B. D., Essaghir, A., Demoulin, J., Catry, É., Neyrinck, A. M., Dewulf, E. M., Sohet, F. M., Portois, L., Clerbaux, L., Carpentier, Y., et al. (2012) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200364 · Cited by 99 · see citing works
“In addition, we have measured the expression of microRNA 33 (miR-33) as it is present in the SREBP-2 primary transcript intron and that it has been shown to modulate hepatic lipid metabolism and to contribute to hepatic lipid accumulation [29].”
BackgroundSelf-citationmiR-33-5p, a novel mechano-sensitive microRNA promotes osteoblast differentiation by targeting Hmga2
Wang, H., Sun, Z., Wang, Y., Hu, Z.-B., Zhou, H., Zhang, L.-C., Hong, B., Zhang, S., & Cao, X.-S. (2016) · Scientific Reports · doi:10.1038/srep23170 · Cited by 95 · see citing works
Cholesterol homeostasis: Researching a dialogue between the brain and peripheral tissues
Gliozzi, M., Musolino, V., Bosco, F., Scicchitano, M., Scarano, F., Nucera, S., Zito, M. C., Ruga, S., Carresi, C., Macrì, R., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105215 · Cited by 92 · see citing works
Regulation of Lipid Homeostasis by the Bifunctional SREBF2-miR33a Locus
Bommer, G. T., & MacDougald, O. A. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.004 · Cited by 92 · see citing works
“For example, the PPARGC1B locus encodes both PGC-1b, a transcriptional coactivator that regulates cellular energy metabolism, and intronic miR-378/378*, which regulate lipid metabolism in adipocytes and respiration in breast cancer cells (Eichner et al., 2010; Gerin et al., 2010a).”
BackgroundInfluentialSelf-citationmiR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways
Wang, H., Sun, T., Hu, J. Y., Zhang, R., Rao, Y., Wang, S., Chen, R., McLendon, R. E., Friedman, A. H., Keir, S. T., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75284 · Cited by 90 · see citing works
“…been studied in the context of cancer, previous reports indicated that miR-33a could act as an important regulator of cholesterol and fatty acid homeostasis via repression of key genes in cholesterol export, high-density lipoprotein metabolism, fatty acid oxidation, and glucose metabolism (16–18).”
Zhang, P., Bai, H., Liu, G., Wang, H., Chen, F., Zhang, B., Zeng, P., Wu, C., Peng, C., Huang, C., et al. (2015) · Toxicology Letters · doi:10.1016/j.toxlet.2015.02.018 · Cited by 89 · see citing works
microRNA control of HDL Metabolism and Function
Rayner, K. J., & Moore, K. (2014) · Circulation Research · doi:10.1161/circresaha.114.300645 · Cited by 89 · see citing works
Kaymak, I., Maier, C. R., Schmitz, W., Campbell, A. D., Dankworth, B., Ade, C. P., Walz, S., Paauwe, M., Kalogirou, C., Marouf, H., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0650 · Cited by 88 · see citing works
“Interestingly, ABCA1 is a target for miRNA-33, which is encoded by an intron within the SREBF2 gene (22, 23).”
BackgroundMicroRNA Regulation of Cholesterol Metabolism
Rotllán, N., & Fernandez-Hernando, C. F. (2012) · Cholesterol · doi:10.1155/2012/847849 · Cited by 86 · see citing works
“Importantly, in vivo inhibition of miR-33 expression leads to a significant increase in plasma HDL levels and the regression of atherosclerosis, thus confirming the physiological effects of miR-33 in regulating lipid metabolism [12, 25, 68, 69].”
BackgroundLjubković, M., Gressette, M., Bulat, C., Ćavar, M., Baković, D., Fabijanić, D., Grković, I., Lemaire, C., & Marinović, J. (2019) · Diabetes · doi:10.2337/db19-0423 · Cited by 84 · see citing works
Simon, T. G., Corey, K. E., Cannon, C. P., Blazing, M. A., Park, J., O’Donoghue, M. L., Chung, R. T., & Giugliano, R. P. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.05.087 · Cited by 82 · see citing works
MicroRNA Modulation of Cholesterol Homeostasis
Fernández-Hernando, C., & Moore, K. J. (2011) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.111.226688 · Cited by 89 · see citing works
miRNAs link metabolic reprogramming to oncogenesis
Hatziapostolou, M., Polytarchou, C., & Iliopoulos, D. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.03.002 · Cited by 80 · see citing works
MicroRNAs regulate lipid metabolism in atherogenesis
Rayner, K. J., Fernández-Hernando, C., & Moore, K. (2012) · Thrombosis and Haemostasis · doi:10.1160/th11-10-0694 · Cited by 83 · see citing works
“Over-expression of miR-33 in hepatocytes down regulates expression of CPT1a, CROT, HADHB and PRKAA1 (AMP Kinase α; AMPKα), decreasing β-oxidation of fatty acids and increasing triglyceride accumulation.”
BackgroundInfluentialBaselga-Escudero, L., Arola-Arnal, A., Pascual-Serrano, A., Ribas-Latre, A., Casanova, E., Salvadó, M., Arola, L., & Bladé, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069817 · Cited by 80 · see citing works
“Additionally, miR-33 plays a crucial role in the regulation of cholesterol metabolism [15,18,38,39].”
BackgroundOxidative stress in atherosclerosis: the role of microRNAs in arterial remodeling.
Zampetaki, A., Dudek, K., & Mayr, M. (2013) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2013.06.025 · Cited by 77 · see citing works
“Their targets include genes involved in cholesterol export and high-density lipoprotein (HDL) synthesis (ABCA1, ABCG1, and NPC1) and fatty acid oxidation (CROT, CPT1a, HADHB) [66,67].”
Ghareghani, P., Shanaki, M., Ahmadi, S., Khoshdel, A., Rezvan, N., Meshkani, R., Delfan, M., & Gorgani‐Firuzjaee, S. (2017) · Obesity Research & Clinical Practice · doi:10.1016/j.orcp.2017.01.004 · Cited by 76 · see citing works
miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux
Ouimet, M. I., Hennessy, E. J., Solingen, C. V., Koelwyn, G. J., Hussein, M. A., Ramkhelawon, B., Rayner, K. J., Temel, R. E., Matic, L. P., Hedin, U., et al. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.307282 · Cited by 77 · see citing works
“miR-33a/b are coexpressed with the SREBF1/2 genes and coordinately repress genes involved in cholesterol efflux, RCT and HDL biogenesis (ABCA1, ABCG1, ABCB11, NPC1, and ATP8B1), as well as fatty acid oxidation (HADHB, CPT1A, CROT, and AMPK).(10,11,15) miR-27b represses genes involved in cholesterol efflux and HDL meta…”
BackgroundA microRNA’s journey to the center of the mitochondria
Macgregor-Das, A. M., & Das, S. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00714.2017 · Cited by 76 · see citing works
ncRNAs: New Players in Mitochondrial Health and Disease?
Gušić, M., & Prokisch, H. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00095 · Cited by 74 · see citing works
Ho, P., Chang, K., Chuang, Y.-S., & Wei, L. (2011) · The FASEB Journal · doi:10.1096/fj.10-179267 · Cited by 73 · see citing works
A pathway approach to investigate the function and regulation of SREBPs
Daemen, S., Kutmon, M., & Evelo, C. T. (2013) · Genes & Nutrition · doi:10.1007/s12263-013-0342-x · Cited by 68 · see citing works
Dual Role of MicroRNAs in NAFLD
Ceccarelli, S., Panera, N., Gnani, D., & Nobili, V. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14048437 · Cited by 66 · see citing works
“molecules as AKT and ERK [50,51].”
Karunakaran, D., Richards, L., Geoffrion, M., Barrette, D., Gotfrit, R. J., Harper, M., & Rayner, K. J. (2015) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.306404 · Cited by 65 · see citing works
“Two copies of the intronic microRNAs (miRNAs) located within the genes encoding sterol regulatory element–binding proteins 1 and 2 (SREBP-1 and SREBP-2), miR-33a/b (miR-33 in mice) collectively repress the expression of cholesterol efflux proteins, ATP-binding cassette A1 (ABCA1) and ABCG1, and genes involved in fatty…”
BackgroundGenetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis
Price, N. L., Miguel, V., Ding, W. J., Singh, A. K., Malik, S., Rotllán, N., Moshnikova, A., Toczek, J., Zeiss, C. J., Sadeghi, M. M., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.131102 · Cited by 67 · see citing works
“…biosynthesis. miR-33a and miR-33b are cotranscribed along with their host genes and work in a concerted manner by targeting genes involved in cholesterol efflux ( ABCA1 , ABCG1 ) (24, 25) and FAO ( CPT1a , CROT , HADHB ) (26, 27). miR-33 is highly expressed in human and mouse kidneys (24, 25).”
Lin, X., Luo, J., Zhang, L., & Zhu, J. (2013) · Gene Expression · doi:10.3727/105221613x13776146743262 · Cited by 66 · see citing works
“Some co-regulated miRNAs are cotranscribed (44).”
InfluentialTraver, S., Assou, S., Scalici, E., Haouzi, D., Al-Edani, T., Belloc, S., & Hamamah, S. (2014) · Human Reproduction Update · doi:10.1093/humupd/dmu031 · Cited by 66 · see citing works
“…which are located within the sterol regulatory element-binding protein 1 and 2 (SREBP 1 and 2) genes, regulate cholesterol and lipid metabolism in concert with their host genes (Gerin et al., 2010; Horie et al., 2010; Marquart et al., 2010; Najafi-Shoushtari et al., 2010; Davalos et al., 2011).”
BackgroundMicroRNA modulation of lipid metabolism and oxidative stress in cardiometabolic diseases
Aranda, J. F., Madrigal‐Matute, J., Rotllán, N., & Fernandez-Hernando, C. F. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.014 · Cited by 66 · see citing works
“MiR-33a and miR-33b also contribute to the regulation of fatty acid metabolism, modulating the expression of carnitine palmitoyltransferase 1A (CPT1A), carnitine O-octanyltransferase (CROT), and hydroxyacylCoA dehydrogenase-3-ketoacyl-CoA thiolase-enoyl-CoA hydratase (trifunctional protein) β-subunit (HADHB) [25,26].”
Li, C., Gong, D., Chen, L., et al. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.05.055 · Cited by 65 · see citing works
Lipid metabolism as a target for cancer drug resistance: progress and prospects
Wang, Z., Wang, Y., Li, Z., Xue, W., Hu, S., & Kong, X. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1274335 · Cited by 66 · see citing works
“Furthermore, miR-33a and miR-33b have been found to inhibit the synthesis of fatty acid oxidase, which leads to a reduction in intracellular lipid renewal (Dávalos et al., 2011; Gerin et al., 2010).”
Micro-RNAs and High-Density Lipoprotein Metabolism
Canfrán‐Duque, A., Lin, C., Goedeke, L., Suárez, Y., & Fernandez-Hernando, C. F. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.307028 · Cited by 64 · see citing works
“Work over the past years has identified miRNAs as important regulators of HDL-cholesterol (HDL-C) metabolism. miRNAs control most of the steps of RCT including HDL biogenesis, cellular cholesterol efflux, hepatic HDL-C uptake, and bile acid synthesis and secretion.18 In addition to their role in regulating HDL-C metab…”
InfluentialMicroRNAs in obesity-associated disorders
Abente, E. J., Subramanian, M., Ramachandran, V., & Najafi-Shoushtari, S. H. (2015) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2015.09.018 · Cited by 63 · see citing works
The role of miRNAs in cardiovascular disease risk factors
Buie, J. N. J., Goodwin, A., Cook, J., Halushka, P., & Fan, H.-K. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.09.067 · Cited by 59 · see citing works
Lu, H., Zhou, X., Kwok, H., Dong, M., Liu, Z., Poon, P.-Y., Luan, X., & Wong, R. N. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00783 · Cited by 62 · see citing works
“Antagonism of miR-33 upregulates ATP-binding cassette transporter A1 (ABCA1) expression and promotes cholesterol efflux to ApoA-I, a key step in regulating reverse cholesterol transport (Gerin et al., 2010; Rayner et al., 2010).”
BackgroundMatoušková, P., Hanousková, B., & Skálová, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041199 · Cited by 63 · see citing works
Kostopoulou, F., Malizos, K., Papathanasiou, I., & Tsezou, A. (2015) · Arthritis Research & Therapy · doi:10.1186/s13075-015-0556-y · Cited by 57 · see citing works
“It regulates the expression of genes involved in cholesterol export and high-density lipoprotein (HDL) biogenesis (ABCA1, ABCG1 and NPC1) [23-25], fatty acid oxidation (CPT1A, CROT, HADHB and AMPKa), bile secretion (ABCB11 and ATP8B1) and insulin signaling (IRS2 and SIRT6) [26-28].”
BackgroundProfibrotic effect of miR-33a with Akt activation in hepatic stellate cells
Li, Z., Ou-Yang, P.-H., & Han, X.-P. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.09.018 · Cited by 60 · see citing works
Cholesterol cholelithiasis: part of a systemic metabolic disease, prone to primary prevention
Ciaula, A. D., Wang, D. Q. ‐., & Portincasa, P. (2018) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2019.1549988 · Cited by 61 · see citing works
- Authors
- Gerin, I., Clerbaux, L.-A., Haumont, O., Lanthier, N., Das, A. K., Burant, C. F., Leclercq, I. A., MacDougald, O. A., & Bommer, G. T.
- Affiliations
- de Duve Institute (BE)
- UCLouvain (BE)
- Michigan Medicine (US)
- University of Michigan (US)
- Corresponding author
- Bommer, Guido T.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 285
- Issue
- 44
- Pages
- 33652-33661
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2962463
- OpenAlex
- W2012616814
- Cited by
- 382
- References
- 60
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 14 · 2023: 16 · 2022: 17 · 2021: 29 · 2020: 15 · 2019: 18 · 2018: 24 · 2017: 25 · 2016: 42 · 2015: 28 · 2014: 36 · 2013: 50 · 2012: 23
- FWCI
- 29.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Funders
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
- National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK089503, R01 DK051563, DK-51563, P30 DK089503)
- Michigan Nutrition Obesity Research Center, Medical School, University of Michigan
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- miR-33, SREBP2, intronic microRNA, ABCA1, cholesterol export, fatty acid beta-oxidation, CPT1A, HADHB, lipid homeostasis, SREBP, protein synthesis inhibition
- MeSH terms
- Animals, Cholesterol, Fatty Acids, Gene Expression Regulation, Humans, Introns, Male, Mice, Inbred C57BL, Phospholipids, Lentivirus, MicroRNAs, Mice, Sterol Regulatory Element Binding Protein 2
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