The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index; 9 of the 46 sources its claims cite were checked for support.
Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA
Open accessAbstract
Low-density lipoprotein receptor (LDLR) is a key regulator of the metabolism of plasma low-density lipoprotein cholesterol (LDL-C), the elevated levels of which are associated with an increased risk of cardiovascular disease. Therefore, enhancing LDLR expression represents a potent treatment strategy for hypercholesterolemia. Here, we report that in cultured human hepatoma cells, triciribine, a highly selective AKT inhibitor, increases the stability of LDLR mRNA, an event that translates into upregulation of cell-surface LDLR levels and induction of cellular LDL uptake. This effect of triciribine requires ERK activity and is partially dependent on the intervening sequence between the AU-rich elements ARE3 and ARE4 in LDLR 3′UTR. We also show that triciribine downregulates the expression of PCSK9 mRNA and blunts the secretion of its protein. Notably, triciribine was found to potentiate the effect of mevastatin on LDLR protein levels and activity. We also show that primary human hepatocytes respond to triciribine by increasing the expression of LDLR. Furthermore, a pilot experiment with mice revealed that a two-weeks treatment with triciribine significantly induced the hepatic expression of LDLR protein. These results identify triciribine as a novel LDLR-elevating agent and warrant further examination of its potential as a hypocholesterolemic drug either as monotherapy or in combination with statins.
Overview
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Written from the paper’s full text.
TL;DR
Triciribine, a selective AKT inhibitor, increases LDLR protein and LDL uptake in hepatic cells by stabilizing LDLR mRNA and reducing PCSK9 expression. It also potentiates mevastatin and induces hepatic LDLR in primary human hepatocytes and mice.
Key findings
- In HepG2 cells, triciribine dose-dependently increased LDLR protein up to 5 µM, with 1 µM used sub-maximally; induction began within 4 hours and continued to 14 hours. It increased cell-surface LDLR and DiD-LDL internalization.
- Triciribine increased LDLR mRNA stability, raising LDLR mRNA half-life from about 1.9 hours to approximately 4.8 hours; this required ERK activity, since U0126 inhibited the effect. Deletion of the intervening sequence between ARE3 and ARE4 partially alleviated the triciribine effect by 30%, and replacement with TFRC sequence inhibited it by 25%.
- Triciribine reduced PCSK9 and HMGCR mRNA and attenuated secreted PCSK9; it also enhanced mevastatin-induced LDLR protein and LDL uptake.
- Triciribine phosphate mimicked triciribine by increasing LDLR protein, stabilizing LDLR mRNA, and inducing DiD-LDL uptake. Primary human hepatocytes responded at higher concentrations, and C57BL/6J mice treated daily with 1 or 2 mg/kg triciribine for two weeks showed significantly increased hepatic LDLR protein.
Methods
- Cultured HepG2, hTERT-immortalized human hepatocytes (IHH), HeLa, and primary human hepatocytes were treated with triciribine or triciribine phosphate under sterol-fed (FBS) or sterol-starved (LPDS) conditions; effects were measured by Western blotting, qPCR, luciferase reporter assays, flow cytometry, confocal microscopy, and PCSK9 ELISA.
- Mechanistic assays included SREBP-2 siRNA knockdown, actinomycin D mRNA stability measurements, ZsGreen1-LDLR 3′UTR wild-type and deletion constructs, and MEK/ERK inhibition with U0126.
- In vivo, 6–8 week old male C57BL/6J mice were given daily intraperitoneal triciribine at 1 mg/kg or 2 mg/kg, or vehicle, for two weeks (four mice per group), then hepatic LDLR was analyzed by immunoblotting; statistical significance was assessed by unpaired two-tailed Student’s t-test with p < 0.05.
Limitations
- The paper states that AKT inhibition by triciribine could carry potential adverse side effects and that prospective in vivo experiments are needed to determine whether triciribine alone or with statins evokes negative side effects.
- The paper notes that it cannot formally disprove that triciribine acts as a DNA synthesis inhibitor rather than through AKT inhibition, and that trans-regulatory proteins mediating LDLR mRNA stabilization remain unidentified.
- Evident from the text: the mouse experiment is described as a pilot with only four mice per group, male C57BL/6J mice only, and no plasma lipid, cholesterol, or toxicity outcomes are reported; primary human hepatocytes required higher triciribine concentrations than cell lines.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
9 of 46 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
- Findingcitation
The IVS region of LDLR 3′UTR contains several sites that closely match the consensus signal for m6A methylation.
“our observation that the IVS region contains several sites that closely match the consensus signal for m6A methylation48”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [48] Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646, https://doi.org/10.1016/j.cell.2012.05.003 (2012). source
- Findingown data
Triciribine inhibits the expression of the C-terminal fragment of cleaved SREBP-2.
“This notion is substantiated by the finding that triciribine inhibits the expression of the C-terminal fragment of cleaved SREBP-2 (Supplementary Fig. S3).”
Quote in the paperSubstantial claim - Findingown data
Triciribine significantly enhanced the effect of mevastatin on LDL internalization.
“Similarly, examination of cellular uptake of DiD-LDL showed that triciribine significantly enhanced the effect of mevastatin on LDL internalization.”
Quote in the paperSubstantial claim - Findingown data
Induction of LDLR mRNA is preceded by the kinetics of ERK phosphorylation.
“Of note is the observation that induction of LDLR mRNA is preceded by the kinetics of ERK phosphorylation (see Fig. 1b).”
Quote in the paperNot a substantial claim - Findingown data
Triciribine phosphate exerted a potent stabilizing effect on LDLR mRNA.
“Next, we extended our analysis to the effect of triciribine phosphate on LDLR mRNA stability and found that triciribine phosphate exerted a potent stabilizing effect on LDLR mRNA (Fig. 6b).”
Quote in the paperSubstantial claim
- Findingown data
Triciribine decreases HMGCR and PCSK9 mRNA levels in cells cultured in the presence of LPDS.
“However, triciribine was found to also decrease HMGCR and PCSK9 mRNA levels in cells that were cultured in the presence of LPDS indicating that inhibition of SREBP-2 activity occurs as a direct response to triciribine.”
Quote in the paperSubstantial claim - Findingown data
PCSK9 secretion from HepG2 cells exposed to triciribine was significantly attenuated.
“PCSK9 secretion from cells that were exposed to triciribine was significantly attenuated (Fig. 3b).”
Quote in the paperSubstantial claim - Findingown data
U0126 significantly mitigated the triciribine-induced stabilization of LDLR mRNA.
“As shown in Fig. 5d, U0126 significantly mitigated the triciribine-induced stabilization of LDLR mRNA.”
Quote in the paperSubstantial claim - Findingreasoning
Triciribine enhances the effect of mevastatin on LDLR expression and cellular uptake of LDL.
“Furthermore, the ability of triciribine to enhance the effect of mevastatin on LDLR expression and cellular uptake of LDL suggests that it may also prove to exert an effective hypocholesterolemic effect when used in combination with statins.”
Quote in the paperSubstantial claim - Findingown data
Triciribine inhibits the expression of IRE1α.
“whereas triciribine inhibits the expression of IRE1α (Supplementary Fig. S6).”
Quote in the paperNot a substantial claim - Findingown data
Triciribine phosphate mimics the effect of triciribine on LDLR expression and function in sterol-fed HepG2 cells.
“Figure 6 Triciribine phosphate mimics the effect of triciribine on LDLR expression and function.”
Quote in the paperSubstantial claim - Findingown data
Triciribine increases LDLR levels in cells cultured in either lipoprotein-containing medium or lipoprotein-deficient medium supplemented with statins.
“The ability of triciribine to increase LDLR levels in cells that were cultured in either lipoprotein-containing medium or lipoprotein-deficient medium that were supplemented with statins (Fig. 4), a treatment reported to decrease cellular free cholesterol content55, suggests that triciribine is able to induce LDLR expression irrespective of cellular cholesterol status”
Quote in the paperSubstantial claim - Findingown data
Neither ARE1, ARE2, ARE3, ARE4 nor UCAU deletions had an appreciable impact on the detected fluorescence signal in triciribine-treated cells.
“However, neither ARE1, ARE2, ARE3, ARE4 nor UCAU deletions had an appreciable impact on the detected fluorescence signal in triciribine-treated cells.”
Quote in the paperSubstantial claim - Findingown data
None of the four LDLR mRNA AREs or the cluster of UCAU repeats alone is utilized by triciribine to exert its mRNA-stabilizing effect.
“Examination of ZsGreen1 fluorescence in cells that expressed chimeric ZsGreen1 mRNAs containing either wt or deletion mutants of LDLR 3′UTR revealed that none of the four LDLR mRNA AREs or the cluster of UCAU repeats alone is utilized by triciribine to exert its mRNA-stabilizing effect.”
Quote in the paperSubstantial claim - Findingown data
Treatment with triciribine potently increased cell-surface LDLR levels.
“Fig. 1d shows that treatment with triciribine potently increased cell-surface LDLR levels.”
Quote in the paperSubstantial claim - Findingown data
Triciribine failed to increase LDLR levels in HeLa cells.
“In contrast, triciribine failed to increase LDLR levels in HeLa cells.”
Quote in the paperSubstantial claim - Findingown data
In C57BL/6J mice fed standard chow, daily treatment with triciribine at 1 mg/kg or 2 mg/kg for two weeks significantly increases hepatic LDLR levels.
“Fig. 7b shows that treatment of mice with either doses of triciribine for two weeks significantly increased the levels of hepatic LDLR.”
Quote in the paperSubstantial claim - Findingown data
Cells exposed to triciribine expressed a higher amount of LDLR protein by fluorescence microscopy.
“The immunoblotting results for LDLR were further confirmed by the results obtained with fluorescence microscopy showing that cells exposed to triciribine expressed higher amount of LDLR protein (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Triciribine induces phosphorylation of hepatic ERK in mice.
“Interestingly, triciribine, similar to its effect on ERK phosphorylation in HepG2 cells, induced the phosphorylation of hepatic ERK (Supplementary Fig. S4).”
Quote in the paperNot a substantial claim - Findingown data
Expression of HMGCR mRNA was inhibited by triciribine.
“Similarly, expression of HMGCR mRNA whose gene is also subject to regulation by SREBP-232,33 was inhibited by triciribine (Fig. 3a).”
Quote in the paperNot a substantial claim - Findingown data
Inclusion of wt LDLR 3′UTR in the pmR-ZsGreen1 plasmid potently reduced the amount of ZsGreen1 fluorescence, confirming the destabilizing effect of LDLR 3′UTR in this experimental system.
“As expected, inclusion of wt LDLR 3′UTR in pmR-ZsGreen1 plasmid potently reduced the amount of ZsGreen1 fluorescence, confirming the destabilizing effect of LDLR 3′UTR in this experimental system (Fig. 2e).”
Quote in the paperSubstantial claim - Findingown data
Triciribine significantly increased the stability of LDLR mRNA.
“As shown in Fig. 2d, triciribine significantly increased the stability of LDLR mRNA.”
Quote in the paperSubstantial claim - Findingown data
GSK690693, another selective AKT inhibitor, increases LDLR expression.
“This is primarily because GSK690693, another selective AKT inhibitor, also increases the expression of LDLR (Supplementary Fig. S5).”
Quote in the paperSubstantial claim - Findingown data
Cells transfected with pmR-ZsGreen1-LDLR-3′UTR-wt exhibited a one-fold increase in fluorescence when treated with triciribine.
“Importantly, cells that were transfected with pmR-ZsGreen1-LDLR-3′UTR-wt exhibited a one-fold increase in fluorescence when treated with triciribine.”
Quote in the paperSubstantial claim - Findingown data
Triciribine appears to inhibit cleavage of SREBP-2.
“while berberine has no effect on proteolytic activation of SREBP-211, triciribine appears to inhibit cleavage of SREBP-2 (Supplementary Fig. S3).”
Quote in the paperNot a substantial claim - Findingown data
Triciribine increased the half-life of LDLR mRNA from about 1.9 hours to approximately 4.8 hours.
“Estimation of LDLR mRNA half-life showed that triciribine increased the half-life of LDLR mRNA from about 1.9 hours to approximately 4.8 hours.”
Quote in the paperSubstantial claim - Findingown data
The level of fluorescence expression generated by pmR-ZsGreen1-LDLR-3′UTR-IVS>TFRC was similar to that of pmR-ZsGreen1-LDLR-3′UTR-Del-IVS.
“As shown in Supplementary Fig. S2, the level of fluorescence expression generated by pmR-ZsGreen1-LDLR-3′UTR-IVS>TFRC was similar to that of pmR-ZsGreen1-LDLR-3′UTR-Del-IVS.”
Quote in the paperSubstantial claim - Findingown data
Triciribine retained its ability to induce LDLR mRNA levels in the absence of SREBP-2.
“As shown in Fig. 2c, triciribine retained its ability to induce LDLR mRNA levels in the absence of SREBP-2.”
Quote in the paperSubstantial claim - Findingown data
A pilot experiment with mice revealed that a two-weeks treatment with triciribine significantly induced the hepatic expression of LDLR protein.
“Furthermore, a pilot experiment with mice revealed that a two-weeks treatment with triciribine significantly induced the hepatic expression of LDLR protein.”
Quote in the paperSubstantial claim - Findingown data
Replacement of IVS with the TFRC coding sequence had an inhibitory effect (25%) on triciribine-mediated induction of fluorescence expression that was similar to that of IVS deletion.
“Furthermore, replacement of IVS with the TFRC coding sequence had an inhibitory effect (25%) on triciribine-mediated induction of fluorescence expression that was similar to that of IVS deletion.”
Quote in the paperSubstantial claim - Findingown data
Primary human hepatocytes respond to triciribine by increasing the expression of LDLR.
“We also show that primary human hepatocytes respond to triciribine by increasing the expression of LDLR.”
Quote in the paperSubstantial claim - Findingown data
The onset of LDLR induction by triciribine was preceded by a robust inhibition of AKT activity, as indicated by phosphorylation status of AKT on S473.
“examination of the phosphorylation status of AKT on S473, which serves as an indicator of its kinase activity, showed that the onset of LDLR induction by triciribine was preceded by a robust inhibition of AKT activity (Supplementary Fig. S1).”
Quote in the paperNot a substantial claim - Findingown data
Triciribine elevated LDLR levels in both sterol-fed and sterol-starved HepG2 cells in a dose-responsive manner up to a concentration of 5 μM.
“Figure 1a shows that triciribine elevated the levels of LDLR in both sterol-fed and sterol-starved cells in a dose-responsive manner up to a concentration of 5 µM.”
Quote in the paperSubstantial claim - Findingown data
Treatment of cells with triciribine phosphate strongly upregulated LDLR protein levels.
“As shown in Fig. 6a, treatment of cells with triciribine phosphate strongly upregulated LDLR protein levels.”
Quote in the paperSubstantial claim - Findingown data
Triciribine reduced the levels of PCSK9 mRNA.
“Fig. 3a shows that triciribine reduced the levels of PCSK9 mRNA.”
Quote in the paperSubstantial claim - Findingown data
Triciribine mitigates SREBP-2 transactivation activity.
“Here, we report that triciribine, while mitigating SREBP-2 transactivation activity, increases the stability of LDLR mRNA.”
Quote in the paperSubstantial claim - Findingown data
The induction of LDLR surface expression by triciribine correlated with enhanced internalization of DiD-LDL.
“Importantly, the induction of LDLR surface expression by triciribine correlated with enhanced internalization of DiD-LDL (Fig. 1e).”
Quote in the paperSubstantial claim - Findingown data
Triciribine reduces LDLR promoter activity.
“The finding that triciribine reduces LDLR promoter activity suggests that it exerts an inhibitory effect on SREBP-2 activity.”
Quote in the paperNot a substantial claim - Findingown data
Treatment of cells with both triciribine and mevastatin enhanced the mevastatin-mediated induction of LDLR protein.
“As shown in Fig. 4a, treatment of cells with both triciribine and mevastatin enhanced the mevastatin-mediated induction of LDLR protein.”
Quote in the paperSubstantial claim - Findingown data
IHH cells responded to triciribine treatment with an increased expression of LDLR.
“Similar to HepG2, IHH cells responded to triciribine treatment with an increased expression of LDLR (Fig. 1f).”
Quote in the paperSubstantial claim - Findingown data
Treatment of cells with triciribine led to reduction, rather than induction, of luciferase activity from the pLR1563-luc LDLR promoter construct.
“Surprisingly, treatment of cells with triciribine led to reduction, rather than induction, of luciferase activity (Fig. 2b)”
Quote in the paperSubstantial claim - Findingreasoning
Triciribine's stabilization of LDLR mRNA depends on ERK activity.
“The involvement of ERK in regulation of LDLR mRNA stability and the dependence of triciribine on ERK activity to stabilize LDLR mRNA prompt us to put forward a simple mechanistic explanation for the stabilizing effect of triciribine on LDLR mRNA.”
Quote in the paperSubstantial claim- Rests on an assumption: ERK is involved in regulation of LDLR mRNA stability.
- Findingown data
Treatment of cells with triciribine phosphate led to a significant induction of cellular DiD-LDL uptake.
“As shown in Fig. 6c, treatment of cells with triciribine phosphate led to a significant induction of cellular DiD-LDL uptake.”
Quote in the paperSubstantial claim - Interpretationown data
Triciribine phosphate affects LDLR expression and LDL uptake in a fashion similar to that of triciribine.
“In sum, these results demonstrate that triciribine phosphate affects LDLR expression and LDL uptake in a fashion similar to that of triciribine.”
Quote in the paperSubstantial claim - Premisecitation
LDLR 3′UTR contains cis-regulating elements that modulate the rate of LDLR mRNA degradation through interaction with trans-regulatory RNA binding proteins.
“Embedded within the LDLR 3′UTR are several cis-regulating elements that modulate the rate of LDLR mRNA degradation through their interaction with trans-regulatory RNA binding proteins8,13.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Wilson, G. M., Vasa, M. Z. & Deeley, R. G. Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3′ untranslated region. Journal of lipid research 39, 1025–1032 (1998). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [13] Yashiro, T., Yokoi, Y., Shimizu, M., Inoue, J. & Sato, R. Chenodeoxycholic acid stabilization of LDL receptor mRNA depends on 3′-untranslated region and AU-rich element-binding protein. Biochemical and biophysical research communications 409, 155–159, https://doi.org/10.1016/j.bbrc.2011.04.006 (2011). source
- Interpretationown data
Triciribine exerts its LDLR mRNA-stabilizing effect in part through one or several destabilizing regulatory elements located between ARE3 and ARE4.
“Taken together, these results suggest that triciribine exerts its LDLR mRNA-stabilizing effect in part through one or several destabilizing regulatory elements that are located between ARE3 and ARE4.”
Quote in the paperSubstantial claim - Interpretationown data
In HepG2 cells, triciribine induces LDLR expression through augmentation of LDLR mRNA stability.
“Using in vitro cultures of the human hepatoma cell line HepG2 as a model system to study modulation of LDLR expression, we found that triciribine, a highly specific inhibitor of AKT kinases, induces the expression of LDLR through augmentation of its mRNA stability.”
Quote in the paperSubstantial claim - Interpretationown data
Inhibition of SREBP-2-regulated transcription is a general feature of triciribine.
“These results suggest that inhibition of SREBP-2-regulated transcription is a general feature of triciribine.”
Quote in the paperSubstantial claim - Interpretationown data
Triciribine stabilizes LDLR mRNA in an ERK activity-dependent manner.
“Taken together, these results show that triciribine stabilizes LDLR mRNA in an ERK activity-dependent manner.”
Quote in the paperSubstantial claim - Premisecitation
The effects of triciribine on LDLR mRNA stability and PCSK9 levels were reminiscent of those elicited by berberine and 5-Azacytidine (5-AzaC).
“The effects of triciribine on LDLR mRNA stability and PCSK9 levels were reminiscent of those elicited by berberine and 5-Azacytidine (5-AzaC)11,34,35.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [11] Kong, W. et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature medicine 10, 1344–1351, https://doi.org/10.1038/nm1135 (2004). source
- cites [34] Mnasri, N., Mamarbachi, M., Allen, B. G. & Mayer, G. 5-Azacytidine engages an IRE1alpha-EGFR-ERK1/2 signaling pathway that stabilizes the LDL receptor mRNA. Biochimica et biophysica acta 1861, 29–40, https://doi.org/10.1016/j.bbagrm.2017.11.010 (2018). source
- cites [35] Poirier, S. et al. The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism. The Journal of biological chemistry 289, 18736–18751, https://doi.org/10.1074/jbc.M114.563650 (2014). source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
Triciribine induces the accumulation of LDLR mRNA through induction of its stability.
“Thus, triciribine induces the accumulation of LDLR mRNA through induction of its stability.”
Quote in the paperSubstantial claim - Interpretationreasoning
Triciribine utilizes a post-transcriptional mechanism to increase LDLR mRNA levels.
“These results show that triciribine utilizes a post-transcriptional mechanism to increase LDLR mRNA levels.”
Quote in the paperSubstantial claim - Interpretationown data
Triciribine-mediated induction of LDLR expression occurs as a result of its ability to inhibit AKT activity.
“Although we cannot formally disprove this suggestion, we are inclined to believe that triciribine-mediated induction of LDLR expression occurs as a result of its ability to inhibit AKT activity.”
Quote in the paperSubstantial claim- Rests on an assumption: Triciribine is a highly specific inhibitor of AKT kinases.
- Interpretationreasoning
Triciribine may exert an effective hypocholesterolemic effect when used in combination with statins.
“suggests that it may also prove to exert an effective hypocholesterolemic effect when used in combination with statins.”
Quote in the paperSubstantial claim - Interpretationown data
These results identify triciribine as a novel LDLR-elevating agent.
“These results identify triciribine as a novel LDLR-elevating agent and warrant further examination of its potential as a hypocholesterolemic drug either as monotherapy or in combination with statins.”
Quote in the paperSubstantial claim- Rests on an assumption: Lowering plasma LDL-C levels is the most effective method to prevent development of ASCVD.
- Rests on an assumption: The amount of LDLR expressed in hepatocytes inversely correlates with the level of plasma LDL-C.
- Interpretationown data
Inhibition of SREBP-2 activity occurs as a direct response to triciribine.
“However, triciribine was found to also decrease HMGCR and PCSK9 mRNA levels in cells that were cultured in the presence of LPDS indicating that inhibition of SREBP-2 activity occurs as a direct response to triciribine.”
Quote in the paperSubstantial claim- Rests on an assumption: HMGCR and PCSK9 genes are regulated by SREBP-2.
- Premisecitation
Post-transcriptional regulation of LDLR is mainly achieved through modulation of its mRNA stability.
“The post-transcriptional regulation of LDLR is mainly achieved through modulation of its mRNA stability8–11.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [8] Wilson, G. M., Vasa, M. Z. & Deeley, R. G. Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3′ untranslated region. Journal of lipid research 39, 1025–1032 (1998). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [9] Wilson, G. M., Roberts, E. A. & Deeley, R. G. Modulation of LDL receptor mRNA stability by phorbol esters in human liver cell culture models. Journal of lipid research 38, 437–446 (1997). source
- cites [10] Goto, D. et al. Upregulation of low density lipoprotein receptor by gemfibrozil, a hypolipidemic agent, in human hepatoma cells through stabilization of mRNA transcripts. Arteriosclerosis, thrombosis, and vascular biology 17, 2707–2712 (1997). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [11] Kong, W. et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature medicine 10, 1344–1351, https://doi.org/10.1038/nm1135 (2004). source
- Interpretationown data
Triciribine is able to induce LDLR expression irrespective of cellular cholesterol status.
“suggests that triciribine is able to induce LDLR expression irrespective of cellular cholesterol status”
Quote in the paperSubstantial claim - Interpretationown data
The induction of LDLR by triciribine translates to an increase in LDLR function.
“These results show that the induction of LDLR by triciribine translates to an increase in LDLR function.”
Quote in the paperSubstantial claim - Interpretationown data
Triciribine increases the expression of LDLR under both basal and sterol-deficient culture conditions.
“Thus, triciribine increases the expression of LDLR under both basal and sterol-deficient culture conditions.”
Quote in the paperSubstantial claim - Interpretationreasoning
Triciribine exerts an inhibitory effect on SREBP-2 activity.
“The finding that triciribine reduces LDLR promoter activity suggests that it exerts an inhibitory effect on SREBP-2 activity.”
Quote in the paperSubstantial claim - Interpretationown data
The LDLR-inducing effect of triciribine may be restricted to cells of hepatic origin.
“Taken together, these results suggest that the LDLR-inducing effect of triciribine may be restricted to cells of hepatic origin.”
Quote in the paperSubstantial claim - Premisecitation
The promoter of the PCSK9 gene contains a serum response element (SRE) that makes its transcription subject to regulation by SREBP-2.
“The promoter of PCSK9 gene contains a serum response element (SRE) that makes its transcription subject to regulation by SREBP-231.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Jeong, H. J. et al. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. Journal of lipid research 49, 399–409, https://doi.org/10.1194/jlr.M700443-JLR200 (2008). source
- Interpretationown data
Activation of LDLR gene expression does not account for triciribine-mediated induction of LDLR mRNA levels.
“suggesting that activation of LDLR gene expression does not account for triciribine-mediated induction of LDLR mRNA levels.”
Quote in the paperSubstantial claim - Interpretationown data
Triciribine exerts an LDLR-inducing effect in both primary human hepatocytes and mouse liver.
“Taken together, these results show that triciribine exerts an LDLR-inducing effect in both primary human hepatocytes and mouse liver.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 22
- It may state two separate claims as one. 23
- The quote only partly states this claim. 2
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAKT signaling has been reported to impinge on the LDLR expression machinery.
“although AKT signaling has been reported to impinge on the LDLR expression machinery25,26”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [25] Luu, W., Sharpe, L. J., Stevenson, J. & Brown, A. J. Akt acutely activates the cholesterogenic transcription factor SREBP-2. Biochimica et biophysica acta 1823, 458–464, https://doi.org/10.1016/j.bbamcr.2011.09.017 (2012). source
- cites [26] Du, X., Kristiana, I., Wong, J. & Brown, A. J. Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: a link between a key cell proliferative pathway and membrane synthesis. Molecular biology of the cell 17, 2735–2745, https://doi.org/10.1091/mbc.E05-11-1094 (2006). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationElevated plasma LDL-C is associated with increased risk of developing atherosclerotic cardiovascular disease (ASCVD).
“Elevated plasma low-density lipoprotein cholesterol (LDL-C) is associated with the risk of developing atherosclerotic cardiovascular disease (ASCVD), a condition that accounts for a large proportion of deaths worldwide1–3.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [1] Musunuru, K. & Kathiresan, S. Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis. Circulation research 118, 579–585, https://doi.org/10.1161/circresaha.115.306398 (2016). source
- cites [2] Lewington, S. et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370, 1829–1839, https://doi.org/10.1016/s0140-6736(07)61778-4 (2007). source
- cites [3] World Health Organization. The global burden of disease: 2004 update (WHO, Geneva 2008).
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationCertain trans-regulating factors act as mRNA stabilizers, while others promote mRNA decay.
“Certain trans-regulating factors act as mRNA stabilizers, while others promote mRNA decay14,15.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [14] Matoulkova, E., Michalova, E., Vojtesek, B. & Hrstka, R. The role of the 3′ untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA biology 9, 563–576, https://doi.org/10.4161/rna.20231 (2012). source
- cites [15] Garcia-Maurino, S. M. et al. RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate. Frontiers in molecular biosciences 4, 71, https://doi.org/10.3389/fmolb.2017.00071 (2017). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAt the transcriptional level, LDLR gene expression is controlled by a cholesterol-responsive negative feedback mechanism through SREBP-2.
“At the transcriptional level, LDLR gene expression is controlled by a cholesterol-responsive negative feedback mechanism through sterol regulatory element-binding protein-2 (SREBP-2)6.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] Goldstein, J. L., DeBose-Boyd, R. A. & Brown, M. S. Protein sensors for membrane sterols. Cell 124, 35–46, https://doi.org/10.1016/j.cell.2005.12.022 (2006). source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPost-translational regulation of LDLR is primarily governed by PCSK9, which upon binding to cell-surface LDLR mediates its degradation.
“Post-translational regulation of LDLR is primarily governed by PCSK9 that upon binding to cell-surface LDLR mediates its degradation7.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Lagace, T. A. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Current opinion in lipidology 25, 387–393, https://doi.org/10.1097/mol.0000000000000114 (2014). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationTriciribine phosphate exerts its kinase inhibitory effect by binding to the PH domain of AKT, thereby preventing its recruitment to the plasma membrane.
“Triciribine phosphate exerts it kinase inhibitory effect by binding to the PH domain of AKT, thereby preventing its recruitment to the plasma membrane24.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Berndt, N. et al. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell death and differentiation 17, 1795–1804, https://doi.org/10.1038/cdd.2010.63 (2010). source
The Abstract and Discussion state that TCN-P binds the Akt PH domain and prevents Akt recruitment to the plasma membrane, leading to reduced Akt phosphorylation. But the Results explicitly find that TCN-P does not directly inhibit Akt kinase activity in vitro; the paper describes it as an Akt activation inhibitor, not a direct kinase inhibitor. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAKT proteins regulate a wide range of cellular functions, such as cell cycle progression, apoptosis and intermediary metabolism.
“AKT proteins regulate a wide range of cellular functions, such as cell cycle progression, apoptosis and intermediary metabolism20.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [20] Manning, B. D. & Toker, A. AKT/PKB Signaling: Navigating the Network. Cell 169, 381–405, https://doi.org/10.1016/j.cell.2017.04.001 (2017). source
Probably not a substantial claim.
PremisecitationPCSK9 plays an important role in cholesterol homeostasis as a result of its ability to reduce cell-surface LDLR levels.
“PCSK9 plays an important role in cholesterol homeostasis as a result of its ability to reduce cell-surface LDLR levels7.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Lagace, T. A. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Current opinion in lipidology 25, 387–393, https://doi.org/10.1097/mol.0000000000000114 (2014). source
It may state two separate claims as one.
Findingown dataLuciferase activity was partially inhibited in cells treated with triciribine, whereas it was induced in mevastatin-treated cells.
“As expected, luciferase activity was partially inhibited in cells that were treated with triciribine, whereas it was induced in mevastatin-treated cells (Fig. 4b).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe intervening region between ARE3 and ARE4 of LDLR 3′UTR plays a partial role in basal LDLR mRNA turnover and in the mRNA-stabilizing effect of triciribine.
“Interestingly, examination of ZsGreen1 fluorescence in cells that expressed the chimeric ZsGreen1-LDLR-3′UTR-Del-IVS or ZsGreen1-LDLR-3′UTR-IVS>TFRC revealed that the intervening region between ARE3 and ARE4 plays an partial role in both basal LDLR mRNA turnover, as well as the mRNA-stabilizing effect of triciribine.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTreatment of cells with triciribine led to a rapid induction of ERK phosphorylation within 1 hour, which reached its peak value at 3 hours and then decreased to levels slightly above basal values.
“Treatment of cells with triciribine led to a rapid induction of ERK phosphorylation (within 1 hour) which reached its peak value at 3 hours after which it decreased to levels slightly above basal values (Fig. 5a).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTriciribine inhibits HMGCR and PCSK9 mRNA levels.
“This idea is corroborated by the inhibitory effect of triciribine on HMGCR and PCSK9 mRNA levels, whose genes are also regulated by SREBP-2.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTriciribine induces LDLR protein levels in cultured primary adult human hepatocytes, at concentrations higher than those needed to exert a similar effect in cell lines.
“Triciribine induced LDLR levels in primary human hepatocytes, albeit at concentrations higher than those that were needed to exert a similar effect in cell lines (Fig. 7a).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCells co-treated with triciribine and mevastatin contained somewhat lower levels of luciferase activity than cells treated with mevastatin alone, but expressed higher levels of LDLR mRNA.
“Importantly, although cells that were co-treated with triciribine and mevastatin contained somewhat lower levels of luciferase activity than cells that were treated with mevastatin alone, they expressed higher levels of LDLR mRNA, apparently as a consequence of the LDLR mRNA-stabilizing effect of triciribine.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDeletion of IVS in LDLR 3′UTR augmented ZsGreen1 levels in untreated cells and partially alleviated (30%) the effect of triciribine on the expression of ZsGreen1 fluorescence.
“In contrast, deletion of IVS in LDLR 3′UTR not only augmented ZsGreen1 levels in untreated cells, but also partially alleviated (30%) the effect of triciribine on the expression of ZsGreen1 fluorescence.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLDLR was significantly induced within 4 hours after triciribine treatment and continued to increase until 14 hours, after which triciribine exhibited a slight loss of its LDLR-inducing effect.
“LDLR was significantly induced within 4 hours after triciribine treatment and continued to increase until 14 hours after which triciribine exhibited a slight loss of its LDLR-inducing effect (Fig. 1b).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataLDLR mRNA was rapidly induced by triciribine in sterol-fed HepG2 cells, reached a maximum level at about 6 hours, and then gradually declined to approximately half its peak level by the end of the experiment.
“As shown in Fig. 2a, LDLR mRNA was rapidly induced by triciribine in sterol-fed HepG2 cells, and reached a maximum level at about 6 hours after which it gradually declined to approximately half its peak level by the end of the experiment.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataThe region between ARE3 and ARE4 (IVS) in the LDLR 3′UTR is disproportionally AU-rich.
“close inspection of LDLR 3′UTR sequence showed the region between ARE3 and ARE4, referred to herein as intervening sequence (IVS), to be disproportionally AU-rich.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataU0126 abrogated the phosphorylation of ERK both in the absence and presence of triciribine, an event that correlated with inhibition of triciribine-mediated induction of LDLR protein and LDLR mRNA.
“U0126 was found to abrogate the phosphorylation of ERK both in the absence or presence of triciribine, an event that correlated with inhibition of triciribine-mediated induction of LDLR protein and LDLR mRNA (Fig. 5b,c).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationLDLR mRNA is a labile transcript that contains a 2.5 kb-long 3′ untranslated region (3′UTR).
“LDLR mRNA is a labile transcript that contains a 2.5 kb-long stretch of 3′ untranslated region (3′UTR)9,12.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Wilson, G. M., Roberts, E. A. & Deeley, R. G. Modulation of LDL receptor mRNA stability by phorbol esters in human liver cell culture models. Journal of lipid research 38, 437–446 (1997). source
- cites [12] Yamamoto, T. et al. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 39, 27–38 (1984). source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationLDLR is an integral membrane protein most abundantly expressed in the liver, where it binds to and removes LDL-C from the circulation by endocytosis.
“Low-density lipoprotein receptor (LDLR) is an integral membrane protein that is most abundantly expressed in the liver, where it binds to and removes LDL-C from the circulation by endocytosis4,5.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science (New York, N.Y.) 232, 34–47 (1986). source
- cites [5] Dietschy, J. M., Turley, S. D. & Spady, D. K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. Journal of lipid research 34, 1637–1659 (1993). source
It may state two separate claims as one.
Interpretationown dataTriciribine is an effective LDLR-inducing agent that induces LDLR expression and reduces PCSK9 levels.
“Here, we report identification of a new agent, triciribine, as an effective LDLR-inducing agent that not only induces the expression of LDLR but also reduces PCSK9 levels.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe LDLR mRNA-stabilizing effect of triciribine not only compensates for its hampering effect on SREBP-2 activity, but also contributes to its stimulating effect on mevastatin-mediated induction of LDLR mRNA.
“This result indicates that the LDLR mRNA-stabilizing effect of triciribine not only compensates for its hampering effect on SREBP-2 activity, but also contributes to its stimulating effect on mevastatin-mediated induction of LDLR mRNA.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSterol-starved cells have lower cholesterol content than sterol-fed cells.
“Sterol-starved cells have lower cholesterol content than sterol-fed cells27,28.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Ishitsuka, R., Saito, T., Osada, H., Ohno-Iwashita, Y. & Kobayashi, T. Fluorescence image screening for chemical compounds modifying cholesterol metabolism and distribution. Journal of lipid research 52, 2084–2094, https://doi.org/10.1194/jlr.D018184 (2011). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [28] Robertson, D. L. & Poznansky, M. J. The effect of non-receptor-mediated uptake of cholesterol on intracellular cholesterol metabolism in human skin fibroblasts. The Biochemical journal 232, 553–557 (1985). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
PremisecitationLDLR 3′UTR associates with the mRNA-stabilizing factor HuR and with decay-promoting factors ZFP36L1, ZFP36L2, KSRP, hnRNP D and hnRNP I.
“For instance, LDLR 3′UTR has been shown to associate with not only the mRNA-stabilizing factor, human antigen R (HuR), but also with decay-promoting factors, such as ZFP36 ring finger protein-like 1 and –like 2 proteins (ZFP36L1 and ZFP36L2), KH-type splicing regulatory protein (KSRP) as well as the D and I members of the heterogeneous nuclear ribonucleoprotein family (hnRNP D and hnRNP I)16–18.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] Yashiro, T., Nanmoku, M., Shimizu, M., Inoue, J. & Sato, R. 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element. Atherosclerosis 226, 95–101, https://doi.org/10.1016/j.atherosclerosis.2012.09.033 (2013). source
- cites [17] Adachi, S. et al. ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway. Nucleic acids research 42, 10037–10049, https://doi.org/10.1093/nar/gku652 (2014). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [18] Li, H. et al. Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements. Journal of lipid research 50, 820–831, https://doi.org/10.1194/jlr.M800375-JLR200 (2009). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe AKT family consists of three highly homologous members, AKT1, AKT2 and AKT3, which exhibit differential tissue-specific expression.
“The AKT family of phospholipid-binding serine/threonine protein kinases consists of three highly homologous members, AKT1, AKT2 and AKT3, which exhibit a differential tissue-specific expression19.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Liao, Y. & Hung, M. C. Physiological regulation of Akt activity and stability. American journal of translational research 2, 19–42 (2010).
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe phosphorylated form of triciribine, triciribine phosphate, is currently in clinical testing as an anti-neoplastic agent.
“In its capacity as an inhibitor of AKT, the phosphorylated form of triciribine, triciribine phosphate, is currently in clinical testing as an anti-neoplastic agent22,23.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] Yang, L. et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer research 64, 4394–4399, https://doi.org/10.1158/0008-5472.can-04-0343 (2004). source
- cites [23] Schweinsberg, P. D., Smith, R. G. & Loo, T. L. Identification of the metabolites of an antitumor tricyclic nucleoside (NSC-154020). Biochemical pharmacology 30, 2521–2526 (1981). source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
Study design and conductown dataIn Fig 7a, primary human hepatocytes were analyzed by Western blotting; one representative experiment of two is shown.
“One representative experiment of two is shown.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenExperiments were performed in accordance with institutional guidelines and were approved by The Norwegian Animal Research Authority.
“Experiments were performed in accordance with institutional guidelines and were approved by The Norwegian Animal Research Authority.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAbnormal AKT kinase activity is implicated in the etiology of a number of diseases, such as cancer.
“Consequently, abnormal AKT kinase activity is implicated in the etiology of a number of diseases, such as cancer, making it an attractive target for kinase inhibitor-based drug development20.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Manning, B. D. & Toker, A. AKT/PKB Signaling: Navigating the Network. Cell 169, 381–405, https://doi.org/10.1016/j.cell.2017.04.001 (2017). source
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataWestern blot analysis in Fig 6a was based on four independent experiments.
“The left panel shows one representative blot from four independent experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAKT isoforms share a common structure consisting of an N-terminal pleckstrin homology (PH) domain, a central kinase domain and a C-terminal hydrophobic motif.
“The AKT isoforms share a common structure that consists of an N-terminal pleckstrin homology (PH) domain, a central kinase domain and a C-terminal hydrophobic motif19.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Liao, Y. & Hung, M. C. Physiological regulation of Akt activity and stability. American journal of translational research 2, 19–42 (2010).
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOnce inside the cell, triciribine is converted to triciribine phosphate by adenosine kinase.
“Once inside the cell, triciribine is converted to triciribine phosphate by adenosine kinase21.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Wotring, L. L. et al. Mechanism of activation of triciribine phosphate (TCN-P) as a prodrug form of TCN. Cancer treatment reports 70, 491–497 (1986).
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationTriciribine is a tricyclic analogue of purine that was initially identified as an inhibitor of DNA synthesis.
“One such inhibitor is triciribine, a tricyclic analogue of purine which was initially identified as an inhibitor of DNA synthesis21.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Wotring, L. L. et al. Mechanism of activation of triciribine phosphate (TCN-P) as a prodrug form of TCN. Cancer treatment reports 70, 491–497 (1986).
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataIn Fig 7b, each group consisted of four mice.
“each group consisted of four mice”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationTriciribine shares with berberine and 5-AzaC the traits of inhibition of DNA synthesis, induction of ERK activity, stabilization of LDLR mRNA, and inhibition of PCSK9 expression.
“Interestingly, triciribine shares a number of similar traits with berberine and 5-AzaC: 1) inhibition of DNA synthesis, 2) induction of ERK activity, 3) stabilization of LDLR mRNA and 4) inhibition of PCSK9 expression11,34,35,49–51.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [11] Kong, W. et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature medicine 10, 1344–1351, https://doi.org/10.1038/nm1135 (2004). source
- cites [34] Mnasri, N., Mamarbachi, M., Allen, B. G. & Mayer, G. 5-Azacytidine engages an IRE1alpha-EGFR-ERK1/2 signaling pathway that stabilizes the LDL receptor mRNA. Biochimica et biophysica acta 1861, 29–40, https://doi.org/10.1016/j.bbagrm.2017.11.010 (2018). source
- cites [35] Poirier, S. et al. The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism. The Journal of biological chemistry 289, 18736–18751, https://doi.org/10.1074/jbc.M114.563650 (2014). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationOnce inside the cell, triciribine is converted to its active phosphorylated derivative, triciribine phosphate, which is currently in phase II human clinical trials.
“Once inside the cell, triciribine is converted to its active phosphorylated derivative, triciribine phosphate that is currently in phase II human clinical trials21,36–38.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [21] Wotring, L. L. et al. Mechanism of activation of triciribine phosphate (TCN-P) as a prodrug form of TCN. Cancer treatment reports 70, 491–497 (1986).
- cites [36] ClinicalTrials.gov. NCT02930109: A Study of PTX-200 (Triciribine) Plus Cytarabine in Refractory or Relapsed Acute Leukemia, https://ClinicalTrials.gov/show/NCT02930109 (2016).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [37] ClinicalTrials.gov. NCT01697293: Triciribine Phosphate, Paclitaxel, Doxorubicin Hydrochloride, and Cyclophosphamide in Treating Patients With Stage IIB-IV Breast Cancer, https://ClinicalTrials.gov/show/NCT01697293 (2012).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [38] ClinicalTrials.gov. NCT01690468: PTX-200 and Carboplatin in Ovarian Cancer, https://ClinicalTrials.gov/show/NCT01690468 (2012).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
Lowering plasma LDL-C levels is the most effective method to prevent development of ASCVD.
“Therefore, lowering of plasma LDL-C levels is the most effective method to prevent development of ASCVD.”
The paper relies on this without support.
The amount of LDLR expressed in hepatocytes inversely correlates with the level of plasma LDL-C.
“Therefore, the amount of LDLR expressed in hepatocytes inversely correlates with the level of plasma LDL-C.”
The paper relies on this without support.
The mechanism by which AKT signaling impinges on LDLR expression remains to be elucidated.
“the mechanism by which it does so remains to be elucidated.”
The paper relies on this without support.
PCSK9 exerts its inhibitory effect on LDLR following its secretion into the extracellular milieu.
“PCSK9 exerts its inhibitory effect on LDLR following its secretion into the extracellular milieu.”
The authors state this as an assumption.
Inhibition of AKT by triciribine could carry a potential for adverse side effects.
“it is justified to assume that inhibition of AKT by triciribine could carry a potential for adverse side effects.”
The paper relies on this without support.
HMGCR and PCSK9 genes are regulated by SREBP-2.
“whose genes are also regulated by SREBP-2”
The paper relies on this without support.
Triciribine is a highly specific inhibitor of AKT kinases.
“triciribine, a highly specific inhibitor of AKT kinases”
The paper relies on this without support.
ERK is involved in regulation of LDLR mRNA stability.
“The involvement of ERK in regulation of LDLR mRNA stability”
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?
Different research groups have identified more than ten different compounds that enhance LDLR mRNA stability and subsequently increase LDLR protein levels, although the mechanisms and specificity are not fully understood.
“Adding to the complexity of LDLR mRNA regulation, different research groups have identified more than ten different compounds that enhance LDLR mRNA stability and subsequently increase LDLR protein levels, although the mechanism(s) behind these effects and how specific they are is not yet fully understood [19,21,24,32,[35][36][37][38][39][40][41].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [19]
Several compounds known to increase LDLR mRNA stability directly have also been reported to decrease expression of SREBP-regulated genes, including PCSK9, exhibiting a dual effect.
“Interestingly, while these compounds are known to increase LDLR mRNA stability directly, several have also been reported to decrease the expression of SREBP-regulated genes, including PCSK9, thus exhibiting a dual effect that could have significant implications for cholesterol management [19,35,42].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [19]
USP2 regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL.
“It has been reported that USP2 can regulate the deubiquitination of LDLR.13)”
From USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination (2020) · cites this paper as [15]
The Introduction describes LDLR regulation through PCSK9-mediated degradation and mRNA stability, while the Discussion focuses on triciribine's effect on LDLR mRNA stability. Searches for USP2-mediated deubiquitination and IDOL found no passage addressing either mechanism, so our copy does not verify the attributed claim. Page numbers were not available in the indexed passages. (LLM, conf=0.76)
Experimental — accuracy not yet measuredOther studies have not been able to definitively identify a single cis-element responsible for the stabilizing effect on the LDLR 3′UTR, even after deletion of several different functional segments within the LDLR 3′UTR.
“However, other studies have not been able to definitively identify a single cis-element responsible for this stabilizing effect on the LDLR 3′UTR, even after deletion of several different functional segments within the LDLR 3′UTR [19,32,41].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [19]
Triciribine (TCN) increases the stability of LDLR mRNA downstream of ERK in human hepatoma cells (HepG2).
“Triciribine (TCN), which is a highly selective AKT inhibitor, increases the stability of LDLR mRNA downstream of extracellular signal-regulated kinase (ERK) in human hepatoma cells (HepG2).”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [12]
TCN shares similarities to berberine, AICAR, and chenodeoxycholic acid by stabilizing LDLR mRNA through an ERK1/2-dependent pathway involving the LDLR 3′UTR.
“While the mechanism of LDLR mRNA stabilization by canadine and gemfibrozil is still unknown, triciribine (TCN) shares similarities to berberine, AICAR, and chenodeoxycholic acid by stabilizing LDLR mRNA through an ERK1/2-dependent pathway, and involve the LDLR 3′UTR [5,8,12,14].”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [12]
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.
Figure 1b is cited for mRNA kinetics but measures protein
MinorThe text cites Figure 1b for the kinetics of LDLR mRNA induction, but the Figure 1b caption says the cells were analyzed by immunoblotting for LDLR protein. LDLR mRNA kinetics are described in Figure 2a.
“Of note is the observation that induction of LDLR mRNA is preceded by the kinetics of ERK phosphorylation (see Fig. 1b).”
“(b) HepG2 cells were cultured as in a and then treated with or without 1 μM triciribine, harvested at the indicated time points and then analyzed by immunoblotting.”
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Metadata
- Authors
- Bjune, K., Wierød, L., & Naderi, S.
- Affiliations
- Oslo University Hospital (NO)
- Corresponding author
- Naderi, Soheil
- Venue
- Scientific Reports
- Published
- 2018-11-01
- Volume
- 8
- Issue
- 1
- Pages
- 16174-16174
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6212527
- OpenAlex
- W2898478418
- Cited by
- 36
- References
- 53
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 3
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of Ulsan
- Universitetet i Oslo
- Nasjonalforeningen for Folkehelsen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- triciribine, LDL receptor, LDL uptake, AKT inhibition, ERK signaling, AU-rich elements, 3' untranslated region, PCSK9, mevastatin, hypercholesterolemia, hepatocytes
- MeSH terms
- Proprotein Convertase 9, Animals, Cells, Cultured, Gene Expression Regulation, Humans, Hypercholesterolemia, Cholesterol, LDL, Liver, Receptors, LDL, Ribonucleosides, RNA, Messenger, Hepatocytes, Proto-Oncogene Proteins c-akt, Mice, Hep G2 Cells, Primary Cell Culture, AU Rich Elements
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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