The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index; 2 of the 28 sources its claims cite were checked for support.
A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes
Open accessAbstract
Cholesterol synthesis and lipoprotein uptake are tightly coordinated to ensure that the cellular level of cholesterol is adequately maintained. Hepatic dysregulation of these processes is associated with pathological conditions, most notably cardiovascular disease. Using a genetic approach, we have recently identified the E3 ubiquitin ligase MARCH6 as a regulator of cholesterol biosynthesis, owing to its ability to promote degradation of the rate-limiting enzymes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE). Here, we present evidence for MARCH6 playing a multifaceted role in the control of cholesterol homeostasis in hepatocytes. We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program. Accordingly, loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. Unexpectedly, this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR). Finally, we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6-induced phenotype. Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
MARCH6 acts as an endogenous inhibitor of SREBP-driven cholesterol synthesis genes and also suppresses IDOL; loss of MARCH6 increases SREBP and LXR target expression but reduces LDLR protein and LDL uptake via IDOL-mediated lysosomal degradation. This identifies a MARCH6-IDOL E3 circuit that uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes.
Key findings
- Silencing MARCH6 increased SREBP-driven reporters 8- to 10-fold in HepG2 cells; mutation of the SRE in the LDLR proximal promoter prevented this regulation, and MARCH6 loss increased SREBP2 target mRNAs in HepG2 and more prominently in IHH cells.
- Despite increased LDLR mRNA, MARCH6 silencing decreased DyLight 488-labeled LDL uptake in HepG2 and Huh7 cells and reduced LDLR protein in HepG2, Huh7, and IHH cells; LDLR-GFP expressed from a constitutive promoter was also reduced, indicating a posttranscriptional mechanism.
- Bafilomycin A1, but not MG132, rescued LDLR levels after MARCH6 silencing; a PCSK9-blocking antibody up to 100 µg/ml did not reverse the LDLR reduction, whereas IDOL knockout or cosilencing prevented it. MARCH6 silencing also induced IDOL mRNA and other LXR target genes and reduced VLDLR.
- The authors conclude that MARCH6 loss increases IDOL expression, which promotes lysosomal degradation of LDLR, thereby uncoupling increased cholesterol synthesis from lipoprotein uptake.
Methods
- Cultured human hepatocyte-like cell lines HepG2, Huh7, and IHH, plus HEK293T and SNB19 cells, were used with siRNA knockdown, CRISPR/Cas9-generated IDOL knockout HepG2 cells, and plasmid transfections.
- Assays included SREBP luciferase reporters, qPCR, immunoblotting, immunoprecipitation, DyLight 488-labeled LDL uptake with confocal microscopy and fluorescence quantification, PCSK9 ELISA, and PCSK9-blocking antibody treatment.
- Statistical analysis used t tests for two groups or one-way ANOVA for grouped analysis, with error bars indicating standard deviations.
Limitations
- Stated: the SREBP transcriptional effect of MARCH6 was limited to hepatic-origin cells and not apparent in nonhepatic cell lines, with the responsible hepatocyte-specific factor unknown; no changes in SREBP2 precursor or processing were detected by immunoblotting (data not shown); intracellular PCSK9 levels in HepG2 and Huh7 cells were insufficient to critically evaluate processing/secretion; IDOL regulation by LXR is species-specific, so the MARCH6-IDOL network is anticipated to be predominantly active in human hepatocytes; no MARCH6 association with plasma LDL cholesterol has yet been reported in genome-wide association studies.
- Evident from the text: the work relies on cultured cell lines and knockdown/knockout approaches without in vivo animal or human validation; activation of LXR by mevalonate pathway intermediates is explicitly speculative; some immunoblots are representative of limited independent experiments (e.g., LDLR-GFP immunoblots from two independent experiments in triplicate).
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
2 of 28 cited sources checked · 2 supported · 0 flagged
- Premisecitation
Hepatic regulation of IDOL transcription by LXRs displays a species-specific divergence.
“Hepatic regulation of IDOL transcription by LXRs displays a species-specific divergence (42).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [42] source
- Findingown data
Silencing of MARCH6 robustly increased the expression of IDOL.
“It was therefore unexpected to find that silencing of MARCH6 also robustly increased the expression of IDOL.”
Quote in the paperSubstantial claim - Findingown data
MARCH6 knockdown increases SRE-Luc reporter activity in Huh7 cells.
“was also apparent in Huh7 cells, another hepatocyte-like cell line (see Fig. S1B).”
Quote in the paperSubstantial claim - Findingown data
The increase in IDOL mRNA following MARCH6 silencing is not due to increased mRNA stability, as it is sensitive to actinomycin D.
“This was not a result of increased mRNA stability since the increase in IDOL mRNA was sensitive to the transcription inhibitor actinomycin D (see Fig. S4B).”
Quote in the paperNot a substantial claim - Findingown data
Independent single siRNAs targeting MARCH6 also increase the SRE-Luc reporter in HepG2 and Huh7 cells.
“we confirmed that independent single siRNAs targeting MARCH6 expression also increased the SRE-Luc reporter in HepG2 (Fig. 1C) and Huh7 hepatocytes (see Fig. S1B).”
Quote in the paperNot a substantial claim
- Findingown data
MG132 has no effect on LDLR level when MARCH6 is silenced.
“the proteasome inhibitor MG132 had no effect in this assay”
Quote in the paperSubstantial claim - Findingown data
PCSK9 mRNA is increased by loss of MARCH6 expression.
“its mRNA is increased by loss of MARCH6 expression (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
Accumulation of extracellular PCSK9 does not account for the MARCH6-induced degradation of the LDLR.
“Accumulation of extracellular PCSK9 does not account for the MARCH6-induced degradation of the LDLR.”
Quote in the paperSubstantial claim - Findingown data
Loss of MARCH6 causes redistribution of LDLR-GFP from the plasma membrane to an intracellular vesicular compartment.
“loss of MARCH6 expression led to a marked redistribution of the protein from the plasma membrane to an intracellular vesicular compartment (Fig. 5C).”
Quote in the paperSubstantial claim - Findingreasoning
LDLR mRNA levels are increased in HepG2 and IHH cells following MARCH6 silencing.
“The LDLR is an SREBP2-regulated gene, and accordingly its levels are increased in HepG2 and IHH cells following silencing of MARCH6.”
Quote in the paperSubstantial claim- Rests on an assumption: The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
- Findingown data
Silencing MARCH6 increases the transcriptional activity of SREBP reporters (SRE-Luc, HMGCS-Luc, and LDLR4000-Luc) 8- to 10-fold in HepG2 cells.
“Effective silencing of MARCH6 in these cells, however, led to a dramatic increase in the transcriptional activity of all three reporters (8-to 10-fold increase) but not of the empty luciferase construct.”
Quote in the paperSubstantial claim - Findingown data
In HepG2 cells stably overexpressing LDLR-GFP, silencing MARCH6 reduces LDLR-GFP abundance.
“In these cells, silencing of MARCH6 reduced the abundance of LDLR-GFP (Fig. 5A and B).”
Quote in the paperSubstantial claim - Findingown data
Inhibition of PCSK9-induced degradation of the LDLR using an effective blocking antibody failed to reverse the LDL phenotype.
“However, inhibition of PCSK9-induced degradation of the LDLR using an effective blocking antibody failed to reverse the LDL phenotype.”
Quote in the paperSubstantial claim - Findingown data
Cosilencing IDOL partially counteracts the siMARCH6-induced decrease in the chimeric receptor.
“cosilencing IDOL could partially counteract the siMARCH6-induced decrease in the level of the chimeric receptor.”
Quote in the paperSubstantial claim - Findingown data
Several other LXR-regulated genes displayed altered expression in response to MARCH6 silencing.
“In addition to IDOL, several other LXR-regulated genes also displayed altered expression in response to MARCH6 silencing.”
Quote in the paperNot a substantial claim - Findingown data
Cosilencing IDOL and MARCH6 by siRNA in HepG2 and Huh7 cells prevents the decrease in LDLR.
“Similar results were also obtained by using siRNA technology to cosilence IDOL and MARCH6 in HepG2 and Huh7 cells (see Fig. S5B).”
Quote in the paperSubstantial claim - Findingown data
Silencing MARCH6 in HEK293 cells does not alter processing or secretion of PCSK9.
“neither processing nor secretion of PCSK9 was altered (see Fig. S3A in the supplemental material).”
Quote in the paperNot a substantial claim - Findingown data
MARCH6 knockdown increases SRE-luciferase activity in a dose-dependent manner.
“The effect of MARCH6 knockdown on SRE-luciferase activity was dose dependent (see Fig. S1A in the supplemental material)”
Quote in the paperSubstantial claim - Findingown data
Silencing MARCH6 substantially decreases uptake of DyLight 488-labeled LDL into HepG2 and Huh7 cells.
“silencing of MARCH6 substantially decreased uptake of DyLight 488-labeled LDL into HepG2 (Fig. 3A and B) and Huh7 (Fig. 3C) cells as determined by confocal microscopy and quantification of the fluorescence signal in cell lysates.”
Quote in the paperSubstantial claim- Rests on an assumption: The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
- Findingown data
Silencing MARCH6 transcriptionally induces IDOL mRNA in three hepatic cell lines in complete or sterol-depleted medium.
“silencing of MARCH6 resulted in transcriptional induction of IDOL mRNA in the three hepatic cell lines tested when they were cultured in complete or sterol-depleted medium.”
Quote in the paperSubstantial claim - Findingown data
Expression of several other LXR target genes is increased in HepG2 and IHH cells following MARCH6 silencing.
“we observed that expression of several other LXR target genes was also increased in HepG2 and IHH cells following silencing of MARCH6 (Fig. 9A and B).”
Quote in the paperNot a substantial claim - Findingown data
Elevation of IDOL expression is more widespread and also apparent to various degrees in cells of nonhepatic origin (e.g., HEK293 and SNB-19 cells).
“Additionally, in contrast to the cell-type-specific regulation of SREBP signaling by MARCH6, elevation of IDOL expression is more widespread and also apparent to various degrees in cells of nonhepatic origin (e.g., HEK293 and SNB-19 cells).”
Quote in the paperNot a substantial claim - Findingown data
Loss of the SRE element prevents regulation of the LDLR promoter reporter by MARCH6.
“loss of this element prevents regulation of the reporter by MARCH6 (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
The intracellular tail of LDLR is sufficient to confer MARCH6 sensitivity.
“the intracellular tail of the LDLR (in the context of a CD8-LDLR chimeric protein) was sufficient to confer MARCH6 sensitivity (see Fig. S4A in the supplemental material).”
Quote in the paperSubstantial claim - Findingown data
PCSK9 levels in supernatant are markedly increased in HepG2 and Huh7 cells following MARCH6 silencing under sterol depletion.
“Under sterol depletion conditions, when PCSK9 production is turned on, PCSK9 levels in the supernatant were markedly increased in both cell lines in response to loss of MARCH6 expression (Fig. 7A and B).”
Quote in the paperSubstantial claim - Findingreasoning
A functional consequence of MARCH6 silencing is a reduction in the ability of cells to take up LDL due to a decrease in LDLR protein.
“A functional consequence of MARCH6 silencing is a reduction in the ability of cells to take up LDL due to a decrease in LDLR protein.”
Quote in the paperSubstantial claim - Findingown data
MARCH6 expression is not sensitive to cellular sterol status.
“expression of MARCH6 itself was not sensitive to the cellular sterol status (see Fig. S2A in the supplemental material).”
Quote in the paperSubstantial claim - Findingown data
Bafilomycin A1 fully rescues LDLR level when MARCH6 is silenced.
“the lysosomotropic agent bafilomycin A1 fully rescued the level of the LDLR when MARCH6 was silenced (Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
MARCH6 acts as an endogenous inhibitor of SREBP signaling.
“We demonstrate here that MARCH6 acts as an endogenous inhibitor of SREBP signaling, providing a second mechanism by which MARCH6 can influence HMGCR levels: increased transcription.”
Quote in the paperSubstantial claim - Premisecitation
MARCH6-dependent regulation of HMGCR is at least in part posttranscriptional, as HMGCR protein expressed from a constitutive promoter is also subject to MARCH6-dependent regulation.
“This regulation was at least in part posttranscriptional as HMGCR protein expressed from a constitutive promoter was also subject to MARCH6-dependent regulation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
- Interpretationreasoning
The functional E3 circuit linking MARCH6 and IDOL adds an additional, previously unrecognized, feedback mechanism to the control of cellular cholesterol homeostasis.
“This functional E3 circuit linking MARCH6 and IDOL adds an additional, previously unrecognized, feedback mechanism to the control of cellular cholesterol homeostasis.”
Quote in the paperSubstantial claim- Rests on an assumption: Making cholesterol de novo is energetically expensive, and the cheapest option for the cell is to derive premade cholesterol by taking up circulating lipoproteins.
- Premisecitation
A major outcome of MARCH6 loss is an increase in basal levels of HMGCR protein.
“This is in line with our earlier observation indicating that a major outcome of MARCH6 loss is an increase in basal levels of HMGCR protein.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
- Interpretationreasoning
MARCH6 prevents degradation of the LDLR, thereby increasing LDL cholesterol uptake in hepatocytes.
“This in turn (step 4) prevents degradation of the LDLR, thereby (step 5) increasing LDL cholesterol uptake in hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
MARCH6 decreases LDLR level through a posttranscriptional process.
“This result points toward MARCH6 decreasing the level of the LDLR through a posttranscriptional process.”
Quote in the paperSubstantial claim - Interpretationown data
MARCH6 and IDOL form an E3 circuit functionally linking to limit uptake of LDL via the LDLR pathway.
“describe an unexpected E3 circuit functionally linking MARCH6 and IDOL to limit uptake of LDL via the LDLR pathway.”
Quote in the paperSubstantial claim - Interpretationreasoning
Our results implicate IDOL as the mediator of the MARCH6-induced phenotype.
“Rather, our results implicate IDOL as the mediator of the MARCH6-induced phenotype.”
Quote in the paperSubstantial claim - Interpretationreasoning
MARCH6 is a regulator of metabolic flux through the mevalonate pathway.
“The ability of MARCH6 to govern the levels of these two important rate-limiting enzymes in cholesterol biosynthesis positions it as a regulator of metabolic flux through the mevalonate pathway.”
Quote in the paperSubstantial claim - Premisecitation
Loss of MARCH6 increases metabolic flux through the mevalonate pathway due to dysregulated control of the pathway at the level of the rate-limiting enzyme SQLE.
“We have previously reported that loss of MARCH6 increases metabolic flux through the mevalonate pathway due to dysregulated control of the pathway at the level of the rate-limiting enzyme SQLE (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] source
- Interpretationown data
Induction of IDOL is the molecular mechanism underlying the MARCH6-induced decrease in LDLR.
“we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6induced phenotype.”
Quote in the paperSubstantial claim - Interpretationreasoning
MARCH6 influences HMGCR levels via increased transcription.
“We demonstrate here that MARCH6 acts as an endogenous inhibitor of SREBP signaling, providing a second mechanism by which MARCH6 can influence HMGCR levels: increased transcription.”
Quote in the paperSubstantial claim - Interpretationreasoning
The multifaceted function of MARCH6 in cholesterol homeostasis in hepatocytes involves both transcriptional and posttranscriptional mechanisms.
“In conclusion, we describe here the multifaceted function of MARCH6 in cholesterol homeostasis in hepatocytes, which involves both transcriptional and posttranscriptional mechanisms.”
Quote in the paperSubstantial claim - Interpretationown data
The decrease in cellular lipoprotein uptake is induced by enhanced lysosomal degradation of LDLR.
“this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR).”
Quote in the paperSubstantial claim - Interpretationreasoning
The functional MARCH6-IDOL network will be predominantly active in human hepatocytes.
“We therefore anticipate that the functional MARCH6-IDOL network will be predominantly active in human hepatocytes.”
Quote in the paperSubstantial claim - Interpretationown data
A MARCH6-dependent mechanism uncouples cholesterol synthesis from lipoprotein uptake.
“Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake.”
Quote in the paperSubstantial claim- Rests on an assumption: The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
- Premisecitation
Loss of MARCH6 activity enhances production of nonsaponifiable lipids by the mevalonate pathway.
“As a result, loss of MARCH6 activity enhances production of nonsaponifiable lipids by the mevalonate pathway.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
- Probably not a substantial claim. 12
- The quote only partly states this claim. 3
- It may state two separate claims as one. 18
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe SREBP pathway is activated when cellular cholesterol levels decline as a means to increase cholesterol synthesis and uptake.
“The SREBP pathway is activated when cellular cholesterol levels decline as a means to increase cholesterol synthesis and uptake (4).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [4] source
The quote only partly states this claim.
Findingown dataSilencing MARCH6 increases expression of SREBP2 target genes in HepG2 and IHH cells under both complete and sterol-depleted conditions.
“This also resulted in increased expression of a panel of studied SREBP2 targets in HepG2 cells (Fig. 2), more prominently evident in IHH cells, which is consistent with them being more metabolically responsive (20).”
- Also stated in: § RESULTS · plain
“Notably, the increase was apparent when cells were cultured in both complete medium and under sterol depletion conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
- Also stated in: § RESULTS · plain
It may state two separate claims as one.
Findingown dataIn control cells, silencing MARCH6 increases SQLE protein and decreases LDLR.
“In control cells, silencing MARCH6 increased SQLE protein and decreased the level of the LDLR (Fig. 8B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSilencing MARCH6 reduces MARCH6 mRNA and increases SQLE protein in hepatic cell lines.
“Silencing MARCH6 in hepatic cell lines reduced its mRNA levels and increased the protein level of its degradation target, SQLE (see Fig. S2B and C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNo changes in the levels of the SREBP2 precursor protein or in SREBP2 processing were detected by immunoblotting in the studied cells.
“However, we think that this is unlikely as we were unable to detect changes in the levels of the SREBP2 precursor protein and in SREBP2 processing by immunoblotting in the studied cells (data not shown).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
FindingcitationIDOL expression decreases in hepatic cells cultured in sterol depletion medium.
“As previously reported, we found that IDOL expression decreased in hepatic cells cultured in sterol depletion medium (Fig. 8A) (10).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
It may state two separate claims as one.
Findingown dataLDLR protein is dramatically reduced following MARCH6 silencing in HepG2, Huh7, and IHH cells, and this reduction is not overcome by sterol depletion.
“we found that LDLR protein was dramatically reduced following silencing of MARCH6, a reduction that could not be overcome by forced activation of the SREBP transcriptional program via sterol depletion (Fig. 4).”
Quote in the paperSubstantial claim- Rests on an assumption: The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
It may state two separate claims as one. The quote only partly states this claim.
Findingown dataMARCH6 silencing specifically reduces LDLR without affecting transferrin receptor, while increasing SQLE.
“the effect of MARCH6 silencing was specific, as abundance of the transferrin receptor remained largely unchanged and that of SQLE increased, as expected.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper may give no reason why it holds.
Study design and conductnone givenThe PCSK9 neutralizing antibody effectively blocks PCSK9-induced degradation of the LDLR.
“However, inhibition of PCSK9-induced degradation of the LDLR using an effective blocking antibody failed to reverse the LDL phenotype.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Study design and conductown dataIn IDOL KO cells, LDLR protein is elevated and GW3695 is unable to promote LDLR degradation, confirming IDOL activity is lost.
“In IDOL KO cells, LDLR protein is elevated, and the synthetic LXR ligand GW3695 is unable to promote degradation of the LDLR, confirming that IDOL activity is lost (see Fig. S5A in the supplemental material).”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationSREBPs induce genes for cholesterol biosynthesis and LDLR.
“This results in induction of the full set of genes required for de novo biosynthesis of cholesterol via the mevalonate pathway and of the low-density lipoprotein receptor (LDLR) that is required for uptake of LDL-derived cholesterol (7,8).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim.
PremisecitationThe SREBP and LXR pathways typically display reciprocal regulation reflecting their opposing action in cellular cholesterol homeostasis.
“Typically, the SREBP and LXR pathways display reciprocal regulation reflecting their opposing action in cellular cholesterol homeostasis (6,37).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe only transcriptional pathway reported to date to regulate the basal and inducible level of IDOL is that controlled by the sterol-sensing LXRs.
“The only transcriptional pathway reported to date to regulate the basal and inducible level of IDOL is that controlled by the sterol-sensing LXRs (10).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationActivation of SREBPs initiates in the ER and requires two-step cleavage of SREBP in the Golgi compartment to release the mature, transcriptionally active SREBP fragment.
“Activation of SREBPs is a complex process that initiates in the ER and requires the subsequent twostep cleavage of SREBP in the Golgi compartment to release the mature, transcriptionally active, SREBP fragment (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] source
It may state two separate claims as one.
InterpretationreasoningThe MARCH6-mediated network uncouples cholesterol synthesis from lipoprotein uptake, sparing cholesterol synthesis while favoring more cholesterol uptake via the LDL receptor.
“Our newly identified MARCH6-mediated network uncouples these two modes of cellular cholesterol accretion, sparing cholesterol synthesis while favoring more cholesterol uptake via the LDL receptor (graphically summarized in Fig. 10).”
Quote in the paperSubstantial claim- Rests on an assumption: Making cholesterol de novo is energetically expensive, and the cheapest option for the cell is to derive premade cholesterol by taking up circulating lipoproteins.
It may state two separate claims as one.
Interpretationown dataMARCH6 is an endogenous inhibitor and negative transcriptional regulator of the SREBP transcriptional program in hepatocyte-like cells.
“We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program.”
- Also stated in: § Abstract · plain
“We identify MARCH6 as a negative regulator of SREBP2-mediated transcription and describe an unexpected E3 circuit functionally linking MARCH6 and IDOL to limit uptake of LDL via the LDLR pathway.”
- Also stated in: § RESULTS · hedged
“In aggregate, these results suggest that MARCH6 is a negative transcriptional regulator of the SREBP pathway in these cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
- Also stated in: § Abstract · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPCSK9 binds LDLR ectodomain and directs lysosomal degradation by preventing recycling.
“The secreted protein PCSK9 binds the ectodomain of the LDLR, and by a mechanism not yet fully elucidated directs the receptor toward lysosomal degradation by preventing its recycling to the plasma membrane (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] source
It may state two separate claims as one.
PremisecitationMARCH6 can also regulate the level of HMGCR, positioning it as an important regulator of flux through the mevalonate pathway.
“In our previous study, we reported that in addition to controlling the levels of SQLE, MARCH6 could also regulate the level of HMGCR, thereby positioning it as an important regulator of flux through the mevalonate pathway (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] source
Probably not a substantial claim.
PremisecitationIDOL is implicated in lysosomal targeting and degradation of LDLR.
“the E3 ligase IDOL, which has also been implicated in lysosomal targeting and degradation of the LDLR (28,33,34).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenImmunoblots are representative of three independent experiments.
“Immunoblots are representative of three independent experiments.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationIn human and primate hepatocytes, IDOL is robustly regulated by LXR activation, yet this does not occur in rodent hepatocytes.
“In human and primate hepatocytes, IDOL is robustly regulated by LXR activation, yet this does not occur in rodent hepatocytes for reasons presently unclear.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] source
Probably not a substantial claim.
PremisecitationMARCH6 controls stability of SQLE, a rate-limiting enzyme in cholesterol synthesis, in a cholesterol-dependent manner.
“We have recently reported that MARCH6, an ERAD-associated E3 (36), controls stability of SQLE, a rate-limiting enzyme in cholesterol synthesis, in a cholesterol-dependent manner (16).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
It may state two separate claims as one.
InterpretationreasoningLoss of MARCH6 in hepatocytes induces a complex cholesterol phenotype in which both the SREBP and LXR pathways are activated.
“Thus, loss of MARCH6 in hepatocytes induces a complex cholesterol phenotype in which both the SREBP and LXR pathways are activated.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataResults represent the mean ± SD from four (Huh7) or eight (HepG2) experiments.
“Results represent the mean Ϯ SD from four (Huh7) or eight (HepG2) experiments.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
PremisecitationSilencing MARCH6 elevates basal levels of HMGCR.
“we also found that the silencing of MARCH6 regulates the basal levels of HMGCR, comparable to what was shown for the E3 HRD1 (16,19).”
Quote in the paperSubstantial claim0 of 2 sources checkedIt may state two separate claims as one.
InterpretationreasoningIncreased IDOL-mediated degradation of the LDLR likely explains why secreted PCSK9 accumulates in MARCH6-silenced cells; decreased LDLR prevents clearance of PCSK9 via the LDLR pathway.
“Increased IDOL-mediated degradation of the LDLR also likely explains why secreted PCSK9 accumulates in MARCH6-silenced cells; decreased LDLR prevents clearance of PCSK9 via the LDLR pathway, as also suggested previously (41).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] source
It may state two separate claims as one.
PremisecitationLXRs induce cholesterol efflux and limit LDL uptake by inducing IDOL.
“LXRs induce cholesterol efflux pathways (e.g., via the transporters ABCA1 and ABCG1) and limit LDL uptake by inducing expression of the E3 ubiquitin ligase (E3)-inducible degrader of the LDLR (IDOL) (6,9,10).”
Quote in the paperSubstantial claim0 of 3 sources checkedIt may state two separate claims as one.
InterpretationreasoningMARCH6 decreases production of sterol agonists for LXR and downregulates gene expression of IDOL.
“However, (step 3) this decreases production of sterol agonists for LXR and downregulates gene expression of IDOL.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningMARCH6 decreases cholesterol synthesis by targeting the key enzymes HMGCR and SQLE and by reducing SREBP-mediated transcriptional activation of cholesterol synthesis genes and the LDLR.
“MARCH6 decreases cholesterol synthesis by (step 1) targeting the key enzymes, HMGCR and SQLE, while also (step 2) reducing SREBP-mediated transcriptional activation of cholesterol synthesis genes and the LDLR.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The hepatocyte-like cell lines HepG2, Huh7, and IHH are adequate models of hepatocyte cholesterol metabolism for the conclusions.
“we determined the mRNA expression levels of a panel of established SREBP2-regulated genes in hepatocytes.”
The paper relies on this without support.
Making cholesterol de novo is energetically expensive, and the cheapest option for the cell is to derive premade cholesterol by taking up circulating lipoproteins.
“We reason that as making cholesterol de novo is energetically expensive, the cheapest option for the cell is to derive premade cholesterol by taking up circulating lipoproteins.”
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?
Hepatic LDLR abundance was unchanged in Marchf6LKO mice.
“Of note, hepatic LDLR abundance was unchanged in the absence in Marchf6LKO, which is different from what was previously reported in hepatoma cell lines as a consequence of concomitant IDOL induction [30].”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [30]
In hepatocyte-like HepG2 cells, the activity of MARCHF6 controls the balance between cholesterol synthesis and uptake via the LDLR pathway.
“Previously, we reported that in hepatocyte-like HepG2 cells the activity of MARCHF6 controls the balance between cholesterol synthesis and uptake via the low density-lipoprotein receptor (LDLR) pathway [30].”
From Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis (2026) · cites this paper as [30]
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.
NHMRC grant number differs between sections
MinorThe acknowledgements give A.J.B.'s NHMRC grant number as 1060515, while the funding information gives Andrew John Brown's NHMRC grant number as 10605151.
“A.J.B. is supported by a grant from the National Health and Medical Research Council (1060515).”
“Department of Health, Australian Government | National Health and Medical Research Council (NHMRC) provided funding to Andrew John Brown under grant number 10605151.”
Fig. 5 immunoblots have fewer experiments than the stated minimum
MinorThe methods say all immunoblots shown represent at least three independent experiments, but the Fig. 5 legend says its immunoblots represent two.
“All immunoblots shown are representative of at least three independent experiments with similar results.”
“Immunoblots are representative of two independent experiments in triplicate.”
PCSK9 supernatant collection duration differs
MinorThe methods specify 24 hours in Opti-MEM before collecting medium for PCSK9 detection, whereas the Fig. 7 procedure specifies 16 hours.
“For detection of PCSK9 in culture medium, cells were washed with phosphate-buffered saline (PBS) and cultured in Opti-MEM (Invitrogen) for 24 h prior to cell lysis.”
“Subsequently, cells were cultured in Opti-MEM for 16 h, supernatants were collected, and total cell lysates were prepared.”
Citations
Cites
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487
An oxysterol signalling pathway mediated by the nuclear receptor LXRα
Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R., & Mangelsdorf, D. J. (1996) · Nature · doi:10.1038/383728a0 · Cited by 1,591
Protein Sensors for Membrane Sterols
Goldstein, J. L., DeBose-Boyd, R. A., & Brown, M. S. (2006) · Cell · doi:10.1016/j.cell.2005.12.022 · Cited by 1,517
Peet, D. J., Turley, S. D., Ma, W., Janowski, B. A., Lobaccaro, J. A., Hammer, R. E., & Mangelsdorf, D. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81432-4 · Cited by 1,428
Liver X receptors as integrators of metabolic and inflammatory signaling
Zelcer, N. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27883 · Cited by 978
Self-citationYokoyama, C., Wang, X., Briggs, M. R., Admon, A., Wu, J., Hua, X., Goldstein, J. L., & Brown, M. S. (1993) · Cell · doi:10.1016/s0092-8674(05)80095-9 · Cited by 975
LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
Zelcer, N., Hong, C., Boyadjian, R., & Tontonoz, P. (2009) · Science · doi:10.1126/science.1168974 · Cited by 848
Self-citationLXR signaling couples sterol metabolism to proliferation in the acquired immune response
Bensinger, S. J., Bradley, M. N., Joseph, S. B., Zelcer, N., Janssen, E. M., Hausner, M. A., Shih, R., Parks, J. S., Edwards, P. A., Jamieson, B. D., et al. (2008) · Cell · doi:10.1016/j.cell.2008.04.052 · Cited by 711
Self-citationSpann, N. J., Garmire, L. X., McDonald, J. G., Myers, D. S., Milne, S. B., Shibata, N., Reichart, D. R., Fox, J. N., Shaked, I., Heudobler, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.054 · Cited by 628
Dubuc, G., Chamberland, A., Wassef, H., Davignon, J., Seidah, N. G., Bernier, L., & Prat, A. (2004) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000134621.14315.43 · Cited by 570
Hua, X., Yokoyama, C., Wu, J., Briggs, M. R., Brown, M. S., Goldstein, J. L., & Wang, X. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.24.11603 · Cited by 544
Maxwell, K. N., Fisher, E. A., & Breslow, J. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409736102 · Cited by 415
Cholesterol, the central lipid of mammalian cells
Maxfield, F. R., & van Meer, G. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.05.004 · Cited by 414
Kikkert, M., Doolman, R., Dai, M., Avner, R., Hassink, G., van Voorden, S., Thanedar, S., Roitelman, J., Chau, V., & Wiertz, E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m307453200 · Cited by 384
Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)
Sharpe, L. J., & Brown, A. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.479808 · Cited by 382
Self-citationJeong, H. J., Lee, H.-S., Kim, K.-S., Kim, Y.-K., Yoon, D., & Park, S. W. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m700443-jlr200 · Cited by 331
Song, B.-L., Sever, N., & DeBose-Boyd, R. A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.08.009 · Cited by 328
Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands
Yang, C., McDonald, J. G., Patel, A. C., Zhang, Y., Umetani, M., Xu, F., Westover, E. J., Covey, D. F., Mangelsdorf, D. J., Cohen, J. C., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603781200 · Cited by 320
Gill, S., Stevenson, J., Kristiana, I., & Brown, A. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.015 · Cited by 304
Self-citationWang, X., Briggs, M. R., Hua, X., Yokoyama, C., Goldstein, J. L., & Brown, M. S. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85266-3 · Cited by 299
Foresti, O., Ruggiano, A., Hannibal-Bach, H. K., Ejsing, C. S., & Carvalho, P. (2013) · eLife · doi:10.7554/elife.00953 · Cited by 205
TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum
Hassink, G. C., Kikkert, M., van Voorden, S., Lee, S., Spaapen, R. M., van Laar, T., Coleman, C. S., Bartee, E., Früh, K., Chau, V., et al. (2005) · Biochemical Journal · doi:10.1042/bj20041241 · Cited by 174
Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase
Jo, Y., & DeBose‐Boyd, R. A. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2010.485605 · Cited by 170
Zelcer, N., Sharpe, L. J., Loregger, A., Kristiana, I., Cook, E. C. L., Phan, L., Stevenson, J., & Brown, A. J. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01140-13 · Cited by 167
Self-citationJo, Y., Lee, P. C.-W., Sguigna, P. V., & DeBose‐Boyd, R. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112831108 · Cited by 161
Hong, C., Duit, S., Jalonen, P., Out, R., Scheer, L., Sorrentino, V., Boyadjian, R., Rodenburg, K. W., Foley, E., Korhonen, L., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123729 · Cited by 142
Self-citationWong, J., Quinn, C. M., & Brown, A. J. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000148707.93054.7d · Cited by 142
Self-citationImmortalized human hepatocytes as a tool for the study of hepatocytic (de-)differentiation
Schippers, I. J., Moshage, H., Roelofsen, H., Müller, M., Heymans, H. S. A., Ruiters, M., & Kuipers, F. (1997) · Cell Biology and Toxicology · doi:10.1023/a:1007404028681 · Cited by 110
PCSK9 as a therapeutic target of dyslipidemia
Seidah, N. G. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220802600715 · Cited by 110
Wang, Y., Huang, Y., Hobbs, H. H., & Cohen, J. C. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m028563 · Cited by 104
Motazacker, M. M., Pirruccello, J. P., Huijgen, R., Do, R., Gabriel, S., Peter, J., Kuivenhoven, J. A., Defesche, J. C., Kastelein, J. J. P., Hovingh, G. K., et al. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehs010 · Cited by 89
Self-citationThe LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.001 · Cited by 87
Scotti, E., Calamai, M., Goulbourne, C. N., Zhang, L., Hong, C., Lin, R. R., Choi, J., Pilch, P. F., Fong, L. G., Zou, P., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01716-12 · Cited by 81
The UPS and downs of cholesterol homeostasis
Sharpe, L. J., Cook, E. C. L., Zelcer, N., & Brown, A. J. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.08.008 · Cited by 74
Self-citationSorrentino, V., Nelson, J. K., Maspero, E., Marques, A. R. A., Scheer, L., Polo, S., & Zelcer, N. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m037713 · Cited by 68
Self-citationLambert, G. C., Petrides, F., Chatelais, M., Blom, D. J., Choque, B., Tabet, F., Wong, G., Rye, K., Hooper, A. J., Burnett, J. R., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.02.538 · Cited by 60
Self-citationSorrentino, V., Fouchier, S. W., Motazacker, M. M., Nelson, J. K., Defesche, J. C., Dallinga‐Thie, G. M., Kastelein, J. J. P., Hovingh, G. K., & Zelcer, N. (2013) · European Heart Journal · doi:10.1093/eurheartj/ehs472 · Cited by 59
Self-citationSorrentino, V., & Zelcer, N. (2012) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283532947 · Cited by 55
Self-citationYamaguchi, S., Yamane, T., Takahashi-Niki, K., Kato, I., Niki, T., Goldberg, M. S., Shen, J., Ishimoto, K., Doi, T., Iguchi‐Ariga, S. M. M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038144 · Cited by 39
Lambert, G. C., Chatelais, M., Petrides, F., Passard, M., Thedrez, A., Rye, K., Schwahn, U., Gusarova, V., Blom, D. J., Sasiela, W. J., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.07.995 · Cited by 30
Self-citationKang, Y.-L., Yochem, J., Bell, L. R., Sorensen, E. B., Chen, L., & Conner, S. D. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-02-0163 · Cited by 30
Sasaki, M., Terao, Y., Ayaori, M., Uto-Kondo, H., Iizuka, M., Yogo, M., Hagisawa, K., Takiguchi, S., Yakushiji, E., Nakaya, K., et al. (2014) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.113.302670 · Cited by 28
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980
Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control
Samant, R. S., Livingston, C. M., Sontag, E. M., & Frydman, J. (2018) · Nature · doi:10.1038/s41586-018-0678-x · Cited by 172
Control of protein degradation by N-terminal acetylation and the N-end rule pathway
Nguyen, K. T., Mun, S.-H., Lee, C. S., & Hwang, C. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0097-y · Cited by 111
Nguyen, K. T., Lee, C.-S., Mun, S.-H., Truong, N. T., Park, S. K., & Hwang, C.-S. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005556 · Cited by 89
MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins
Stefanovic-Barrett, S., Dickson, A. S., Burr, S. P., Williamson, J. C., Lobb, I. T., van den Boomen, D. J. H., Lehner, P. J., & Nathan, J. A. (2018) · EMBO Reports · doi:10.15252/embr.201745603 · Cited by 82
Emerging lysosomal pathways for quality control at the endoplasmic reticulum
Leonibus, C. D., Cinque, L., & Settembre, C. (2019) · FEBS Letters · doi:10.1002/1873-3468.13571 · Cited by 61
Cholesterol Metabolism in Cancer and Cell Death
Chen, F., Lu, Y., Lin, J., Kang, R., & Liu, J. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0340 · Cited by 53
Sharpe, L. J., Howe, V., Scott, N. A., Luu, W., Phan, L., Berk, J. M., Hochstrasser, M., & Brown, A. J. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005069 · Cited by 53
Self-citationEnzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context
Ershov, P., Kaluzhskiy, L. A., Mezentsev, Y. V., Yablokov, E. O., Gnedenko, O. V., & Ivanov, A. S. (2021) · Biomedicines · doi:10.3390/biomedicines9080895 · Cited by 48
Tan, J. M. E., Cook, E. C. L., van den Berg, M., Scheij, S., Zelcer, N., & Loregger, A. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.12.008 · Cited by 46
Self-citationUbiquitin-mediated regulation of sterol homeostasis
van den Boomen, D. J. H., Volkmar, N., & Lehner, P. J. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.04.010 · Cited by 41
The E3 ubiquitin ligase MARCHF6 as a metabolic integrator in cholesterol synthesis and beyond
Scott, N. A., Sharpe, L. J., & Brown, A. J. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2020.158837 · Cited by 16
Self-citationLoregger, A., Raaben, M., Tan, J. M. E., Scheij, S. S., Moeton, M., van den Berg, M., Gelberg-Etel, H., Stickel, E., Roitelman, J., Brummelkamp, T. R., et al. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310002 · Cited by 32
Self-citationThe HDL particle composition determines its antitumor activity in pancreatic cancer
Oberle, R., Kührer, K., Österreicher, T., Weber, F., Steinbauer, S., Udonta, F., Wroblewski, M., Batalla, I. B., Hassl, I., Körbelin, J., et al. (2022) · Life Science Alliance · doi:10.26508/lsa.202101317 · Cited by 31
Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene
Cook, E. C. L., Nelson, J. K., Sorrentino, V., Koenis, D. S., Moeton, M., Scheij, S. S., Ottenhoff, R., Bleijlevens, B., Loregger, A., & Zelcer, N. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172721 · Cited by 31
Self-citationScott, N. A., Sharpe, L. J., Capell-Hattam, I. M., Gullo, S. J., Luu, W., & Brown, A. J. (2020) · Biochemical Journal · doi:10.1042/bcj20190647 · Cited by 31
Self-citationMARCH6 promotes Papillary Thyroid Cancer development by destabilizing DHX9
Liu, Y., Xu, S., Huang, Y. S., Liu, S., Xu, Z.-G., Wei, M., & Liu, J. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.60628 · Cited by 29
The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting
Tan, J. M. E., van der Stoel, M. M., van den Berg, M., van Loon, N. M., Moeton, M., Scholl, E. R., van der Wel, N. N., Kovačević, I., Hordijk, P. L., Loregger, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107944 · Cited by 28
Self-citationThe role of ER-associated degradation and ER-phagy in health and disease
Jeon, Y. J., & Ronai, Z. A. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02501-7 · Cited by 25
The Role of Ubiquitin E3 Ligase in Atherosclerosis
Zhou, Z., Ren, Z., Yan, B., Qu, S.-L., Tang, Z., Wei, D., Liu, L.-S., Fu, M., & Jiang, Z. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327666200306124418 · Cited by 22
Pronk, M. C. A., Majolée, J., Loregger, A., van Bezu, J. S. M., Zelcer, N., Hordijk, P. L., & Kovačević, I. (2019) · Molecular Biology of the Cell · doi:10.1091/mbc.e18-04-0259 · Cited by 21
Self-citationPolyphenols alleviate metabolic disorders: the role of ubiquitin-proteasome system
Gu, W., Wu, G., Chen, G., Meng, X., Xie, Z., & Cai, S. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1445080 · Cited by 19
MARCH6 promotes hepatocellular carcinoma development through up-regulation of ATF2
Sun, J., Dong, Z., Chang, Z., Liu, H., Jiang, Q., Zhang, D., Lu, S., Jia, X., Wu, D., Ge, A., et al. (2021) · BMC Cancer · doi:10.1186/s12885-021-08540-x · Cited by 16
Coates, H. W., Chua, N. K., & Brown, A. J. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2019.08.006 · Cited by 15
Self-citationKang, J. A., & Jeon, Y. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042078 · Cited by 15
Wu, P., Gao, H., Liu, J., Kosma, D. K., Lü, S., & Zhao, H. (2021) · Plant Physiology and Biochemistry · doi:10.1016/j.plaphy.2021.08.021 · Cited by 15
Eberhart, T., Eigner, K., Filik, Y., Fruhwürth, S., Stangl, H., & Röhrl, C. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.110 · Cited by 14
Robert, S., & Sniderman, A. D. (2017) · Journal of Biomedical Research · doi:10.7555/jbr.31.20160139 · Cited by 14
Oommen, D., Kizhakkedath, P., Jawabri, A. A., Varghese, D. S., & Ali, B. R. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.570355 · Cited by 12
E3 Ubiquitin Ligases: Structures, Biological Functions, Diseases, and Therapy
Wang, H., Peng, J., Li, H., Lan, Y., Guo, J., Qiu, Q., & Huang, X. (2025) · MedComm · doi:10.1002/mco2.70528 · Cited by 11
MARCH Proteins Mediate Responses to Antitumor Antibodies
Ablack, J., Ortiz, J., Bajaj, J., Trinh, K., Lagarrigue, F., Cantor, J. M., Reya, T., & Ginsberg, M. H. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901245 · Cited by 11
Yin, J., Xu, J., Chen, C., Ma, X., Zhu, H., Xie, L., Wang, B., Shao, Y., Zhao, Y., Wei, Y., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1191692 · Cited by 10
Role of MARCH E3 ubiquitin ligases in cancer development
Behera, A., Sachan, D., Barik, G. K., & Reddy, A. B. M. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-024-10201-x · Cited by 10
IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China
Adi, D., Abuzhalihan, J., Wang, Y., Baituola, G., Wu, Y., Xie, X., Fu, Z.-Y., Yang, Y., Ma, X., Li, X., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-71241-1 · Cited by 9
Foiling IDOL to Help Control Cholesterol
Brown, A. J., & Hsieh, J. (2016) · Circulation Research · doi:10.1161/circresaha.116.308191 · Cited by 9
Self-citationQuantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome
Jiang, J., & Wang, Y. (2022) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.2c00197 · Cited by 4
Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression
Krishnan, N., Chen, X., Donnelly‐Roberts, D. L., Mohler, E. G., Holtzman, D. M., & Gopalakrishnan, S. M. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00851 · Cited by 4
Xu, S., Donnelly, L., Kober, D. L., Mak, M., & Radhakrishnan, A. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100650 · Cited by 3
Sachdev, V., van Loon, N. M., Kingma, J., Ottenhoff, R., Tan, J. M. E., van den Berg, M., Duijst, S., Jongejan, A., Levels, J. H. M., Rensen, P. C. N., et al. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102379 · Cited by 1
Self-citationUbiquitin E3 ligase mediated regulation of HMG-CoA Reductase
Menzies, S. A. (2017) · Apollo (University of Cambridge) · doi:10.17863/cam.20825
Khalil, Y. A. (2021) · theses.fr (ABES) · doi:10.70675/1964fe3fz37bfz493azb98czc7caecac12cf
Sun, J., Dong, Z., Chang, Z., Liu, H., Jiang, Q., Zhang, D., Lu, S., Jia, X., Wu, D., Ge, A., et al. (2021) · Figshare · doi:10.6084/m9.figshare.15000113
Regulation of cellular functions and diseases by the MARCH E3 ubiquitin ligases
Zhang, Q. P., Qiao, Y.-T., & Li, S. (2026) · Cell Insight · doi:10.1016/j.cellin.2026.100339
Protein M of NADC30-like PRRSV induces MARCH6-mediated K33-linked polyubiquitination of SLA-DRA
Hu, R., Mou, S., Yu, C., Li, J., Shi, W., (532481), Y. Z., Nasir, S., Guo, R., Li, J., Qiu, X., et al. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113478
Squalene epoxidase in cancer: Mechanistic insights, therapeutic potential, and future perspectives
Zhang, Q., Zhang, C., & Liu, D. (2026) · Experimental Cell Research · doi:10.1016/j.yexcr.2026.115166
Regulatory mechanisms of E3 ubiquitin ligases in cholesterol homeostasis
Deng, Q., Hu, Y., Liao, D., & Zhang, C. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154691
Distributed AI agents enable comprehensive discovery of biological insights at scalePreprint
Sun, A., Park, J. J., DeTomaso, D., Kim, S., Liu, A., Shringarpure, S., Kim, K., Thompson, P. C., Shi, T., Wang, Y., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.15.759436
Leitch, E. K., Elumalai, N., Fridén-Saxin, M., Dahl, G., Wan, P., Clarkson, P., Valeur, E., Pairaudeau, G., Boyd, H., & Tavassoli, A. (2018) · Chemical Science · doi:10.1039/c8sc01186a · Cited by 25
Metadata
- Authors
- Loregger, A., Cook, E. C. L., Nelson, J. K., Moeton, M., Sharpe, L. J., Engberg, S., Karimova, M., Lambert, G., Brown, A. J., & Zelcer, N.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- UNSW Sydney (AU)
- AstraZeneca R&D, Gothenburg, Sweden
- Inserm (FR)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2016-01-01
- Volume
- 36
- Issue
- 2
- Pages
- 285-294
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC4719299
- OpenAlex
- W2175246669
- Semantic Scholar
- 129262aadc8db31b35213f5b1d06011b5412ffa7
- Cited by
- 48
- References
- 45
- Citations by year
- 2026: 7 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 2
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- EC | European Research Council (617376)
- Department of Health, Australian Government | National Health and Medical Research Council (10605151)
- Hartstichting (2013T111)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (17.106.355)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- idols, E3 ubiquitin ligase, cholesterol biosynthesis, lipoprotein uptake, cholesterol homeostasis, hepatocytes, SREBP, HMGCR, squalene epoxidase, LDL receptor, lysosomal degradation, cardiovascular disease
- MeSH terms
- Cell Line, Cholesterol, Humans, Lipoproteins, Membrane Proteins, Receptors, LDL, Gene Silencing, Hepatocytes, Ubiquitin-Protein Ligases, Biosynthetic Pathways, Hep G2 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
