Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration
Open accessAbstract
BACKGROUND & AIMS: Constitutive androstane receptor (CAR) transcriptionally regulates xenobiotic detoxification, metabolism, and hepatocyte proliferation. Although CAR activation promotes regeneration and its loss impairs recovery after extreme hepatectomy (86%-90% liver resection), its temporal role during standard liver regeneration following two-thirds partial hepatectomy remains unclear. METHODS: We quantified DNA synthesis, gene expression, and bile acid concentrations and composition in Car knockout and wild-type mice across regenerative time points after partial hepatectomy. RESULTS: Car transcript expression is dynamically regulated during regeneration, peaking at 12 hours and plummeting below basal levels by 72 hours post-partial hepatectomy. Despite this, Car knockout livers regenerate comparably to wild-type livers. Notably, Car knockout mice display an exaggerated increase in hepatic and systemic bile acid levels after partial hepatectomy, revealing an unexpected metabolic role for CAR. Pharmacological reduction of bile acid levels with cholestyramine in Car knockout mice attenuated 5-bromo-2'-deoxyuridine incorporation and proliferation-associated gene expression. Analysis of single-cell RNA sequencing data further showed that Car and its target genes are enriched in hypermetabolic, rather than proliferating, hepatocyte population during regeneration. CONCLUSIONS: CAR exerts a temporally regulated metabolic role during liver regeneration. Car deletion amplifies the post-hepatectomy bile acid surge, which acts as a compensatory pro-proliferative signal to sustain regeneration.
AI snapshot
Written from the paper’s full text.
TL;DR
Constitutive androstane receptor (CAR) is dispensable for hepatocyte proliferation after two-thirds partial hepatectomy in mice, but it constrains the post-hepatectomy bile acid surge. In Car knockout mice, exaggerated bile acids act as a compensatory pro-proliferative signal, and CAR/target genes are enriched in hypermetabolic rather than proliferating hepatocytes.
Key findings
- Car transcript is dynamically regulated after partial hepatectomy, peaking at 12 hours and falling to its lowest level at 36 hours in females or 72 hours in males, then returning to basal by 96 hours.
- Car knockout livers regenerate comparably to wild-type livers after two-thirds partial hepatectomy, with no noticeable differences in body weight, liver weight, or BrdU incorporation regardless of sex; however, male CarKO mice show more pronounced serum AST/ALT at 12 hours.
- Car deletion amplifies the bile acid surge: at 12 hours post-PHx, serum bile acids increased ∼20× in male WT mice versus ∼524× in male CarKO mice, while hepatic bile acids were ∼4× higher in male and ∼2× higher in female CarKO mice.
- Cholestyramine reduced bile acids and attenuated BrdU incorporation and proliferation-associated gene expression in CarKO mice, and scRNA-seq showed Car and its target genes enriched in hypermetabolic hepatocytes rather than proliferating hepatocytes among 18,272 hepatocytes.
Methods
- Male and female CarKO and C57BL/6J WT mice, aged 8–10 weeks, underwent two-thirds partial hepatectomy and were analyzed at 0, 12, 36, 72, and 96 hours; outcomes included BrdU incorporation, qRT-PCR, serum AST/ALT, blood glucose, and bile acid concentrations/composition.
- Bile acids were measured by colorimetric assay and liquid chromatography–mass spectrometry; male mice were also fed a 2% cholestyramine diet for 1 week before partial hepatectomy, and a separate cohort received TCPOBOP (3 mg/kg) or corn oil.
- Published scRNA-seq data (GSE151309) from male WT regenerating and developing livers were reanalyzed with Seurat v3.2.6; 18,272 hepatocytes were classified as quiescent (5328), transition (5137), proliferating (6769), and hypermetabolic (1038). Statistical comparisons used t tests or 1-/2-way ANOVA with Fisher’s LSD post hoc test, with P < .05 considered significant.
Limitations
- The paper states that d4-TMCA was used as the internal standard for all MCA species, so α-, β-, and ω-isomers of MCA or TMCA could not be distinguished.
- Evident from the text: the mechanistic work is in mice after two-thirds partial hepatectomy, the scRNA-seq analysis uses previously published male WT hepatocytes only, and the cholestyramine experiments were performed only in male mice.
- Evident from the text: some experimental groups had small sample sizes (n = 3–4 mice), and sex-specific differences in bile acid homeostasis and regeneration are reported but not fully mechanistically resolved.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
53 of 88 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured
- Premisecitation
CAR activation promotes liver growth via MET and EGFR signaling.
“CAR activation also promotes liver growth via the MET proto-oncogene and epidermal growth factor receptor (EGFR) signaling.23”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Bhushan, 2019, TCPOBOP-induced hepatomegaly and hepatocyte proliferation are attenuated by combined disruption of MET and EGFR signaling, Hepatology source
- Premisecitation
Pharmacological activation of CAR stimulates liver regeneration.
“Although pharmacological activation of CAR has been demonstrated to stimulate liver regeneration,20,24 loss of function studies remain sparse.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [20] Gao, 2021, Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation, Acta Pharm Sin B source
- cites [24] Tschuor, 2016, Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss, J Hepatol source
- Findingcitation
scRNA-seq analysis identified four hepatocyte states after PHx: quiescent (5328), transition (5137), proliferating (6769), and hypermetabolic (1038) among 18,272 hepatocytes.
“Importantly, single-cell transcriptomic analysis identified distinct clusters among 18,272 hepatocytes corresponding to quiescent (5328 hepatocytes), transition (5137 hepatocytes), proliferating (6769 hepatocytes), and hypermetabolic (1038 hepatocytes) states after PHx.6”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chembazhi, 2021, Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver, Genome Res source
The Results sections on cell-type composition and division of labor report 18,272 hepatocytes and classify them into the four named states. Our copy does not give the claimed count for each state (5,328; 5,137; 6,769; and 1,038). The 18,272 cells also include samples from uninjured adult and postnatal livers, not only samples collected after PHx. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
An unintended consequence of accumulating excess BAs is proliferation.
“An unintended consequence of accumulating excess BAs is proliferation.5,36”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science source
- cites [36] Bhushan, 2013, Role of bile acids in liver injury and regeneration following acetaminophen overdose, Am J Pathol source
The ‘Increase in Total Bile Acids and FGF15 mRNA’ section reports that cholic acid supplementation raised bile acid levels, and ‘Mechanisms of Rapid Recovery’ reports greater liver-cell proliferation in supplemented mice after acetaminophen treatment. The claim omits that injury context: the paper says the supplemented mice had no ongoing cell proliferation before acetaminophen treatment, so it does not show that excess bile acids alone cause proliferation. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Findingown data
CHR reduces c-Myc mRNA levels in both WT and CarKO mice post-PHx.
“In line with previous findings that elevated BAs can induce c-Myc expression,37,38 CHR reduced c-Myc mRNA levels in both WT and CarKO mice post-PHx (Figure 9A).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [37] Yang, 2009, Switch from Mnt-Max to Myc-Max induces p53 and cyclin D1 expression and apoptosis during cholestasis in mouse and human hepatocytes, Hepatology source
- cites [38] Yang, 2015, Activation of a novel c-Myc-miR27-prohibitin 1 circuitry in cholestatic liver injury inhibits glutathione synthesis in mice, Antioxid Redox Signal source
- Findingown data
BA composition differs by sex.
“Consistent with previous reports,12,30 we observed sex differences in BA composition (Figure 4C–F).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [12] Lickteig, 2016, Activation of Constitutive Androstane Receptor (CAR) in mice results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver, Toxicol Sci source
- cites [30] Lickteig, 2019, Effects of absence of Constitutive Androstane Receptor (CAR) on bile acid homeostasis in male and female mice, Toxicol Sci source
- Premisecitation
The effects of the CAR-driven c-Myc-Foxm1 axis are not recapitulated in humanized CAR transgenic mice or human hepatocytes.
“these effects are not recapitulated in humanized CAR transgenic mice or human hepatocytes,45, 46, 47”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [45] Niu, 2018, In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets, Nucleic Acids Res source
The Discussion (page unavailable) reports much weaker Myc induction in humanized CAR mice than in wild-type mice, supporting a species difference, but not a complete absence of the effect. The Results (page unavailable) do not establish that a c-Myc–Foxm1 axis fails to occur in human hepatocytes; the paper discusses FOXO3, not Foxm1, in relation to Myc. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [46] Sprenger, 2022, Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver, Arch Toxicol source
The Results (Functional enrichment analysis; page unavailable) report predicted MYC activation in mouse but not human hepatocytes after phenobarbital treatment. The Discussion (page unavailable) reports a clear proliferation-marker increase in wild-type mice but only a non-significant tendency in humanized CAR/PXR mice. These passages support a weaker proliferative response, but do not establish that the specific c-Myc–Foxm1 axis is not recapitulated in humanized CAR transgenic mice. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [47] Plummer, 2019, Cross-species comparison of CAR-mediated procarcinogenic key events in a 3D liver microtissue model, Toxicol Rep source
The Results (Hepatocyte proliferation; page not available) report that phenobarbital induced proliferation in rat liver microtissues but not in human liver microtissues, supporting a narrower human-hepatocyte comparison. The paper does not establish that the c-Myc–Foxm1 axis itself was absent in human hepatocytes, and the retrieved passages do not address humanized CAR transgenic mice. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Expression of genes involved in cell proliferation and BA homeostasis reveals sex differences.
“In addition, the expression of genes involved in cell proliferation and BA homeostasis also revealed sex differences.30”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] Lickteig, 2019, Effects of absence of Constitutive Androstane Receptor (CAR) on bile acid homeostasis in male and female mice, Toxicol Sci source
The Results and Discussion report sex-specific expression of genes involved in bile acid synthesis and transport in CAR-null mice. The passages do not report sex differences in the expression of cell-proliferation genes, so that part of the sentence is unsupported. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Interpretationown data
CAR has a protective function during cholestasis.
“Overall, these findings are consistent with a protective function for CAR during cholestasis.10, 11, 12, 13,54”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [10] Zhang, 2004, The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity, J Biol Chem source
- cites [11] Beilke, 2009, Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice, Drug Metab Dispos source
- cites [12] Lickteig, 2016, Activation of Constitutive Androstane Receptor (CAR) in mice results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver, Toxicol Sci source
- Premisecitation
FXR facilitates liver regeneration via induction of Foxm1.
“whereas FXR facilitates liver regeneration via induction of Foxm1.5,60, 61, 62, 63”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [5] Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science source
- cites [60] Chen, 2010, Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription, Hepatology source
- cites [61] Zhang, 2012, Promotion of liver regeneration/repair by farnesoid X receptor in both liver and intestine in mice, Hepatology source
- Findingown data
Car deletion leads to a bimodal surge in serum and hepatic BAs at 12 and 72 hours compared with male WT mice.
“However, Car deletion led to a bimodal surge in serum and hepatic BAs at 12 and 72 hours compared with male WT mice (Figure 4A and B).”
Quote in the paperSubstantial claim - Findingown data
Liver proliferation is highest at 36 hours post-PHx in both sexes of WT mice.
“As expected, liver proliferation was highest at 36 hours post-PHx in both sexes of WT mice (Figure 2B and C).”
Quote in the paperNot a substantial claim - Findingown data
Car knockout mice display an exaggerated increase in hepatic and systemic bile acid levels after partial hepatectomy.
“Notably, Car knockout mice display an exaggerated increase in hepatic and systemic bile acid levels after partial hepatectomy, revealing an unexpected metabolic role for CAR.”
Quote in the paperSubstantial claim - Findingown data
Car and its target genes are enriched in hypermetabolic, rather than proliferating, hepatocyte population during regeneration.
“Analysis of single-cell RNA sequencing data further showed that Car and its target genes are enriched in hypermetabolic, rather than proliferating, hepatocyte population during regeneration.”
Quote in the paperSubstantial claim - Findingown data
Male CarKO mice maintain a similar proliferative gene expression pattern to WT mice after PHx.
“Male CarKO mice maintained a similar proliferative gene expression pattern to WT mice (Figure 3B–H).”
Quote in the paperSubstantial claim - Findingown data
Foxm1 and cell-cycle genes are comparably expressed in both male and female WT livers after PHx.
“Foxm1 and cell-cycle genes were comparably expressed in both male and female WT livers (Figure 3B–H).”
Quote in the paperNot a substantial claim - Findingnone given
Car deletion amplifies the post-hepatectomy bile acid surge.
“Car deletion amplifies the post-hepatectomy bile acid surge, which acts as a compensatory pro-proliferative signal to sustain regeneration.”
Quote in the paperSubstantial claim - Findingown data
Car knockout livers regenerate comparably to wild-type livers after partial hepatectomy.
“Despite this, Car knockout livers regenerate comparably to wild-type livers.”
Quote in the paperSubstantial claim - Findingown data
In female CarKO mice, higher total BAs are mainly attributed to increased taurine-conjugated BAs.
“Although total BAs were higher in female CarKO mice, this was mainly attributed to increased taurine-conjugated BAs (Figure 5B and D).”
Quote in the paperNot a substantial claim - Findingown data
Pharmacological reduction of bile acid levels with cholestyramine in Car knockout mice attenuates BrdU incorporation and proliferation-associated gene expression.
“Pharmacological reduction of bile acid levels with cholestyramine in Car knockout mice attenuated 5-bromo-2'-deoxyuridine incorporation and proliferation-associated gene expression.”
Quote in the paperSubstantial claim- Rests on an assumption: Cholestyramine's effect on hepatocyte proliferation is mediated specifically by reducing bile acid levels, not by other effects of the drug.
- Findingown data
CHR-fed male CarKO mice show altered expression of genes controlling BA homeostasis.
“Figure 10 CHR-fed male CarKO mice show altered expression of genes controlling BA homeostasis.”
Quote in the paperSubstantial claim - Findingown data
CHR-fed male CarKO mice exhibit decreased expression of cell proliferation genes.
“Figure 9 CHR-fed male CarKO mice exhibit decreased expression of cell proliferation genes.”
Quote in the paperSubstantial claim - Findingown data
In the absence of CAR, an exaggerated BA surge occurs early after PHx.
“Instead, integrative gene expression analyses, BA profiling, and scRNA-seq data mining reveal that CAR activity is enriched in hypermetabolic hepatocytes and that, in the absence of CAR, an exaggerated BA surge occurs early after PHx, promoting liver regeneration in CarKO mice.”
Quote in the paperSubstantial claim - Findingown data
In male WT mice after PHx, Car and its target genes are more highly expressed in hypermetabolic hepatocytes than in quiescent, transition, or proliferative hepatocytes.
“When we examined the different hepatocyte states, we observed higher expression of Car (Figure 12C) and its target genes (Figure 12D) in metabolically hyperactive hepatocytes than those in the quiescent, transition, or proliferative states.”
- Also stated in: § Car and Its Target Genes Are Highly Expressed in Hypermetabolic Hepatocytes After Partial Hepatectomy · plain
“Figure 12 Car and its targets are more highly expressed in hypermetabolic than proliferating hepatocytes after PHx in males.”
Quote in the paperSubstantial claim - Also stated in: § Car and Its Target Genes Are Highly Expressed in Hypermetabolic Hepatocytes After Partial Hepatectomy · plain
- Findingown data
Female WT livers show reduced expression of Bsep and Mrp2/4 at 12 hours that gradually increases at 72 hours after PHx.
“Female WT livers also showed a reduced expression of Bsep and Mrp2/4 at 12 hours that gradually increased at 72 hours (Figure 7B).”
Quote in the paperNot a substantial claim - Findingown data
A specific increase in Mrp4 transcript levels at 72 hours correlates with the rise in serum BAs after PHx.
“Additionally, a specific increase in Mrp4 transcript levels was observed at 72 hours, which correlates with the rise in serum BAs (Figures 4A and 7B).”
Quote in the paperNot a substantial claim - Findingown data
Deletion of Car does not alter ileal BA levels in male mice.
“Figure 11 Deletion of Car alters neither ileal expression of Fxr and Fgf15 transcripts nor BA levels in males.”
Quote in the paperSubstantial claim - Findingown data
Cholestyramine alters systemic and hepatic BA composition in both genotypes, indicated by increased proportions of CA and/or DCA and decreased MCA.
“CHR also altered systemic and hepatic BA composition in both genotypes, indicated by increased proportions of CA and/or DCA and decreased MCA (Figure 8C and D).”
Quote in the paperNot a substantial claim - Findingown data
CAR is dispensable for sustaining hepatocyte proliferation after PHx in CarKO mice.
“Using CarKO mice, we show that CAR is dispensable for sustaining hepatocyte proliferation after PHx.”
Quote in the paperSubstantial claim - Findingown data
Male CarKO livers maintain a hydrophobic BA composition with a lower MCA/CA ratio at different timepoints after PHx.
“Male CarKO livers, however, maintained a hydrophobic BA composition with a lower MCA/cholic acid (CA) ratio at different timepoints after PHx (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
Hepatocyte proliferation measured by BrdU incorporation is intact after two-thirds PHx in CarKO livers.
“In contrast, we observed intact hepatocyte proliferation (measured via BrdU incorporation) after two-thirds PHx in CarKO livers (Figure 2B and C).”
Quote in the paperSubstantial claim - Findingown data
We do not detect CAR-dependent differences in ileal Fxr or Fgf15 expression.
“we do not detect CAR-dependent differences in ileal Fxr or Fgf15 expression (Figure 11B and C)”
Quote in the paperSubstantial claim - Findingown data
Depletion of BAs leads to a more pronounced reduction in hepatocyte proliferation in CarKO mice compared with WT mice.
“Depletion of BAs leads to a more pronounced reduction in hepatocyte proliferation in CarKO mice compared with WT mice (Figure 8E and F)”
Quote in the paperSubstantial claim - Findingown data
Female CarKO mice exhibit BA profiles and liver injury markers comparable to WT controls.
“In contrast, female CarKO mice exhibit BA profiles and liver injury markers comparable to WT controls (Figures 2F and G and 4D and F)”
Quote in the paperSubstantial claim - Findingown data
Basal c-Myc expression is elevated in CarKO livers.
“Unexpectedly, we detect elevated basal expression of c-Myc in CarKO livers (Figure 3A).”
Quote in the paperNot a substantial claim - Findingreasoning
We observed distinct regenerative and metabolic responses between male and female CarKO mice.
“we observed distinct regenerative and metabolic responses between male and female CarKO mice.”
Quote in the paperSubstantial claim - Interpretationown data
Peak Car expression does not coincide with proliferation but rather with the initiation/preparation stage of liver regeneration.
“These data reveal that the peak Car expression does not coincide with proliferation but rather with the initiation/preparation stage.”
Quote in the paperSubstantial claim - Study design and conductown data
Liquid chromatography-mass spectrometry analysis validated the serum BA spike seen in the colorimetric assay.
“Liquid chromatography–mass spectrometry analysis (Figure 5A–D and Table 1, Table 2, Table 3, Table 4) validated the serum BA spike seen in the colorimetric assay (Figure 4A and B).”
Quote in the paperSubstantial claim - Premisecitation
Existing reports suggest impaired regeneration in Car knockout mice post-PHx.
“Existing reports suggest impaired regeneration in Car knockout (CarKO) mice post-PHx,5,24 but the temporal dynamics and metabolic functions of CAR during regeneration are yet to be elucidated.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
CAR has a previously unappreciated metabolic axis that supports the regenerative capacity of the liver.
“Our findings demonstrate that CAR is an important regulator of BA metabolism during PHx and reveal a previously unappreciated metabolic axis of CAR that supports the regenerative capacity of the liver.”
Quote in the paperSubstantial claim- Rests on an assumption: Loss-of-function studies of CAR in liver regeneration are sparse, and the temporal dynamics and metabolic functions of CAR during regeneration are not yet elucidated.
- Interpretationown data
The post-hepatectomy bile acid surge acts as a compensatory pro-proliferative signal to sustain regeneration in Car knockout mice.
“Car deletion amplifies the post-hepatectomy bile acid surge, which acts as a compensatory pro-proliferative signal to sustain regeneration.”
Quote in the paperSubstantial claim- Rests on an assumption: Cholestyramine's effect on hepatocyte proliferation is mediated specifically by reducing bile acid levels, not by other effects of the drug.
- Interpretationown data
CAR has a metabolic role in regulating bile acid homeostasis during liver regeneration after partial hepatectomy.
“CAR exerts a temporally regulated metabolic role during liver regeneration.”
- Also stated in: § Conclusions · plain
“Beyond the established role in detoxification, we uncover that constitutive androstane receptor modulates bile acid homeostasis in regenerating livers after partial hepatectomy.”
- Also stated in: § Lowering Bile Acid Levels in Car Knockout Mice Results in Reduced Liver Proliferation After Partial Hepatectomy · plain
“These findings highlight the importance of CAR in maintaining BA levels during regeneration.”
Quote in the paperSubstantial claim - Also stated in: § Conclusions · plain
- Premisecitation
Acute increases in bile acid levels act as a key pro-regenerative signal for liver regeneration after PHx.
“Notably, acute increases in bile acid (BA) levels act as a key pro-regenerative signal for this process.3, 4, 5”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [3] Doignon, 2011, Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis, J Hepatol source
- cites [4] Pean, 2013, The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice, Hepatology source
- cites [5] Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science source
- Interpretationown data
CAR regulates glucose homeostasis during early liver regeneration.
“Overall, these results demonstrate a metabolic role of CAR in regulating BA and glucose homeostasis during early liver regeneration.”
Quote in the paperSubstantial claim - Interpretationown data
CAR activity is enriched in hypermetabolic hepatocytes.
“Instead, integrative gene expression analyses, BA profiling, and scRNA-seq data mining reveal that CAR activity is enriched in hypermetabolic hepatocytes and that, in the absence of CAR, an exaggerated BA surge occurs early after PHx, promoting liver regeneration in CarKO mice.”
Quote in the paperSubstantial claim - Interpretationown data
The exaggerated BA surge promotes liver regeneration in CarKO mice.
“Instead, integrative gene expression analyses, BA profiling, and scRNA-seq data mining reveal that CAR activity is enriched in hypermetabolic hepatocytes and that, in the absence of CAR, an exaggerated BA surge occurs early after PHx, promoting liver regeneration in CarKO mice.”
Quote in the paperSubstantial claim - Interpretationown data
Regulation of BA transporter genes after PHx is likely CAR-independent.
“This data indicates that the regulation of BA transporter genes after PHx is likely CAR-independent.”
Quote in the paperSubstantial claim - Premisecitation
Prior reports showed delayed or impaired regeneration in CarKO mice after 70% or ~86% PHx.
“Prior reports showed either delayed or impaired regeneration in CarKO mice following 70% or ∼86% PHx,5,24”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
CAR signaling has a role in maintaining metabolic functions in adult hepatocytes, in addition to proliferation.
“These results highlight the role of CAR signaling in maintaining metabolic functions in adult hepatocytes, in addition to proliferation.”
Quote in the paperSubstantial claim - Interpretationown data
CAR has a sex-specific role in regulating hepatic and circulating BA levels and composition.
“Taken together, these results suggest a sex-specific role for CAR in regulating hepatic and circulating BA levels and composition.”
Quote in the paperSubstantial claim - Interpretationown data
CAR has a temporally restricted and metabolically focused role during liver regeneration.
“In this study, we define a temporally restricted and metabolically focused role for CAR during liver regeneration.”
Quote in the paperSubstantial claim - Interpretationown data
The regulation of ileal Fxr and Fgf15 transcript expression is CAR-independent.
“Moreover, CAR activation12 and deficiency30 did not alter this axis, indicating that the regulation of ileal Fxr and Fgf15 transcript expression is CAR-independent.”
Quote in the paperSubstantial claim - Interpretationown data
Reduced BA export can contribute to the initial rise in hepatic BAs after PHx.
“We also examined and found that BA export genes bile salt export pump (Bsep) and multidrug resistance protein 2/3/4 (Mrp2/3/4) exhibited a general reduction after PHx in male WT livers, except for a transient increase in Mrp2 at 36 hours and a 50% derepression of Bsep transcript by 72 hours (Figure 7B), suggesting that the reduced export can also contribute to the initial rise seen in hepatic BAs.”
Quote in the paperSubstantial claim - Interpretationown data
There is a lack of activated FXR signaling in CarKO livers.
“suggesting a lack of activated FXR signaling.”
Quote in the paperSubstantial claim - Interpretationcitation
There are important species-specific differences in CAR effects.
“highlighting important species-specific differences.”
Quote in the paperNot a substantial claim - Premisecitation
Female livers are more sensitive to CAR activation.
“and the fact that female livers are more sensitive to CAR activation,65”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Petrick, 2007, Importance of hepatic induction of constitutive androstane receptor and other transcription factors that regulate xenobiotic metabolism and transport, Drug Metab Dispos source
- Interpretationown data
Intestinal FXR-FGF15 signaling is not a major contributor in this case.
“suggesting that intestinal FXR–FGF15 signaling is not a major contributor in this case.”
Quote in the paperSubstantial claim - Interpretationown data
The BA surge has a proregenerative role.
“Functional interrogation of the BA surge using cholestyramine further supports its proregenerative role.”
Quote in the paperSubstantial claim - Interpretationown data
CAR has a sex-specific role in maintaining BA homeostasis during regeneration.
“revealing a sex-specific role for CAR in maintaining BA homeostasis during regeneration.”
Quote in the paperSubstantial claim - Interpretationown data
Elevated BAs partially compensate for the absence of CAR.
“indicating that elevated BAs partially compensate for the absence of CAR.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 56
Classified as probably not a substantial claim.
PremisecitationCAR is a pleiotropic regulator of liver detoxification, metabolism, proliferation, and hepatomegaly.
“The nuclear receptor, constitutive androstane receptor (CAR; NR1I3), is a pleiotropic regulator of liver detoxification, metabolism, proliferation, and hepatomegaly.7, 8, 9, 10, 11, 12, 13, 14”
Quote in the paperSubstantial claim5 of 8 sources checked- cites [7] Cai, 2021, The xenobiotic receptors PXR and CAR in liver physiology, an update, Biochim Biophys Acta Mol Basis Dis source
- cites [8] Wei, 2000, The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism, Nature source
- cites [9] Eloranta, 2005, Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism, Arch Biochem Biophys source
- cites [10] Zhang, 2004, The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity, J Biol Chem source
- cites [11] Beilke, 2009, Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice, Drug Metab Dispos source
The Discussion reports that CAR regulates bile acid metabolism, and the introductory passage describes its role in bile acid detoxification and bilirubin clearance (pages unavailable). The paper does not substantively address CAR's role in liver proliferation or hepatomegaly; hepatomegaly appears only in the title of a cited reference. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [12] Lickteig, 2016, Activation of Constitutive Androstane Receptor (CAR) in mice results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver, Toxicol Sci source
The Introduction (page unavailable) describes CAR’s role in inducing genes involved in drug and xenobiotic detoxification. The Results section on liver weight and bile flow reports increased liver weight in mice after CAR activation, and the Discussion describes changes in bile-acid metabolism. Our copy does not establish a role for CAR in liver proliferation, so that part of the attributed claim is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [13] Mathur, 2020, Transcriptomic analysis across liver diseases reveals disease-modulating activation of constitutive androstane receptor in cholestasis, JHEP Rep source
The Results section on CAR activation reports regulation of detoxification and metabolic genes and upregulation of cell-cycle-associated transcripts, suggesting a role in proliferation. Our copy does not link CAR to hepatomegaly (liver enlargement), so that part of the attributed claim is unsupported. No page numbers are available in the indexed passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [14] Kim, 2019, Constitutive androstane receptor differentially regulates bile acid homeostasis in mouse models of intrahepatic cholestasis, Hepatol Commun source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA subset of hypermetabolic hepatocytes compensates for the transient loss of metabolic function during liver regeneration after PHx.
“A recent single-cell study characterized the functional heterogeneity within hepatocytes after PHx and identified a subset of hypermetabolic hepatocytes that compensate for the transient loss of metabolic function during regeneration.6”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] Chembazhi, 2021, Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver, Genome Res source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElevated concentrations and a more hydrophilic BA pool promote liver regeneration after PHx.
“Growing evidence shows that elevated concentrations and a more hydrophilic BA pool promote liver regeneration after PHx.4,26,27”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [4] Pean, 2013, The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice, Hepatology source
- cites [26] Bhushan, 2022, The benevolent bile: bile acids as stimulants of liver regeneration, Cell Mol Gastroenterol Hepatol source
In the main text (page not available), the paper says moderate bile-acid supplementation stimulates liver regeneration after partial hepatectomy. It does not say that a more hydrophilic bile-acid pool promotes regeneration, and it emphasizes physiological rather than generally elevated levels. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [27] Zhou, 2022, Rebuttal to: the benevolent bile: bile acids as stimulants of liver regeneration, Cell Mol Gastroenterol Hepatol source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCAR's pro-proliferative role in liver is mediated through induction of c-Myc, Foxm1, and cyclin D1, and modulation of β-catenin and YAP signaling pathways.
“Prior studies have focused primarily on the pro-proliferative role of CAR in the liver, mediated through the induction of factors such as cellular-myelocytomatosis oncogene (c-Myc),15 forkhead box m1 (Foxm1),15 and cyclin D1 (Ccnd1),16 as well as modulation of β-catenin17,18 and Yes-associated protein19, 20, 21, 22 signaling pathways.”
Quote in the paperNot a substantial claim4 of 8 sources checked- cites [15] Blanco-Bose, 2008, C-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia, Hepatology source
- cites [16] Ledda-Columbano, 2000, Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis2-(3,5-Dichloropyridyloxy). benzene, Am J Pathol source
Citation 16 is attached to the cyclin D1 portion of the sentence, not the separately cited factors and pathways. The Discussion (page unavailable) reports rapid induction of cyclin D1 in mouse liver after treatment with TCPOBOP, which the paper says activates CAR. It proposes, but does not establish, that the activated receptor induces cyclin D1; the claim states that mechanism more firmly than the source does. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [17] Braeuning, 2011, Gender-specific interplay of signaling through beta-catenin and CAR in the regulation of xenobiotic-induced hepatocyte proliferation, Toxicol Sci source
- cites [18] Ganzenberg, 2013, The time point of beta-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor, Toxicology source
- cites [19] Kowalik, 2011, Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice, Hepatology source
- cites [20] Gao, 2021, Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation, Acta Pharm Sin B source
- cites [21] Abe, 2018, Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes, Toxicol Sci source
- cites [22] Bhushan, 2021, Yes-associated protein is crucial for constitutive androstane receptor-driven hepatocyte proliferation but not for induction of drug metabolism genes in mice, Hepatology source
May combine two claims.
FindingcitationCAR activation and CAR deficiency did not alter ileal Fxr and Fgf15 transcript expression.
“Moreover, CAR activation12 and deficiency30 did not alter this axis, indicating that the regulation of ileal Fxr and Fgf15 transcript expression is CAR-independent.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [12] Lickteig, 2016, Activation of Constitutive Androstane Receptor (CAR) in mice results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver, Toxicol Sci source
- cites [30] Lickteig, 2019, Effects of absence of Constitutive Androstane Receptor (CAR) on bile acid homeostasis in male and female mice, Toxicol Sci source
Classified as probably not a substantial claim.
PremisecitationA discrepancy between serum and hepatic BA levels occurs during cholestasis secondary to either reduced hepatic BA extraction efficiency in the enterohepatic loop or portosystemic shunts.
“Such a discrepancy is known to occur during cholestasis secondary to either reduced hepatic BA extraction efficiency in the enterohepatic loop or due to portosystemic shunts.28,29”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [28] Ohkubo, 1984, Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis, Gastroenterology source
- cites [29] Pare, 1981, Determinants of serum bile acids in chronic liver disease, Gastroenterology source
The Discussion says that reduced hepatic extraction and extrahepatic shunting can increase peripheral serum bile acids in chronic liver disease. However, the study measured bile acids in portal, hepatic, and peripheral venous blood in patients with alcoholic liver disease; it does not establish a discrepancy between serum and hepatic tissue bile-acid levels specifically during cholestasis. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataCHR-fed WT mice show a reduced number of BrdU-positive nuclei compared with chow-fed WT mice, validating a role for the BA spike in liver regeneration.
“It is pertinent to note that CHR-fed WT mice also showed a reduced number of BrdU-positive nuclei compared with chow-fed WT mice (Figure 8E and F), validating a role for the BA spike in liver regeneration, consistent with previous findings.5,36”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [5] Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science source
- cites [36] Bhushan, 2013, Role of bile acids in liver injury and regeneration following acetaminophen overdose, Am J Pathol source
- Rests on an assumption: Cholestyramine's effect on hepatocyte proliferation is mediated specifically by reducing bile acid levels, not by other effects of the drug.
May combine two claims.
PremisecitationCHR reduces intestinal FXR-FGF15/19 signaling, which indirectly regulates liver regeneration.
“Because CHR has been shown to reduce farnesoid X receptor (FXR)–fibroblast growth factor 15/19 (FGF15/19) signaling in the intestine that indirectly regulates liver regeneration,5,41,42”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [5] Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science source
- cites [41] Naugler, 2014, Bile acid flux is necessary for normal liver regeneration, PLoS One source
The Results section reports that interrupting bile-acid circulation by biliary fistula made intestinal Fgf15 undetectable and attenuated liver regeneration; Asbt-knockout mice likewise had nearly undetectable intestinal Fgf15 and diminished regrowth. The Introduction links intestinal FXR and FGF15 to regeneration, but the paper does not show that CHR itself reduces intestinal FXR–FGF15/19 signaling. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [42] Kong, 2018, Fibroblast growth factor 15-dependent and bile acid-independent promotion of liver regeneration in mice, Hepatology source
The Introduction states that intestinal FXR induces Fgf15/FGF19, which promotes hepatocyte proliferation and liver regeneration. It also reports that bile-acid depletion by cholestyramine decreased liver regeneration, but it does not say that CHR reduces intestinal FXR–FGF15/19 signaling. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHydrophobic BAs are cytotoxic but at tolerated concentrations can promote proliferation, whereas hydrophilic BAs, particularly UDCA and MCA, are cytoprotective.
“Hydrophobic BAs are cytotoxic but at tolerated concentrations can promote proliferation,26,27,31 whereas hydrophilic BAs, particularly ursodeoxycholic acid and MCA, are cytoprotective.32,33”
Quote in the paperNot a substantial claim4 of 5 sources checked- cites [26] Bhushan, 2022, The benevolent bile: bile acids as stimulants of liver regeneration, Cell Mol Gastroenterol Hepatol source
The opening section (page not provided) says increased intracellular bile-acid levels are generally associated with pathogenic outcomes, while bile acids at physiological levels stimulate liver regeneration. That supports the concentration-dependent contrast attributed to this source, but it does not identify hydrophobic bile acids specifically or establish that they are cytotoxic. The hydrophilic-bile-acid clause has separate citations and is not assessed against this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [27] Zhou, 2022, Rebuttal to: the benevolent bile: bile acids as stimulants of liver regeneration, Cell Mol Gastroenterol Hepatol source
The main text (page unavailable) says hydrophobic bile acids induce cytotoxicity and that a taurine conjugate of a slightly hydrophobic bile acid facilitates hepatocyte proliferation. It also says hydrophilic bile acids alleviate liver injury, but does not specify a tolerated concentration for proliferation or identify MCA as protective. Its example of UDCA describes hepatocyte apoptosis rather than directly establishing cytoprotection. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [31] Zhou, 2022, Melanchole: the dark side of bile acids and its cellular consequences, Cell Mol Gastroenterol Hepatol source
The paper’s main text (page unavailable in our copy) says hydrophilic ursodeoxycholic acid protects against oxidative stress and cell death. It does not mention MCA or establish that MCA is cytoprotective. The proliferation clause has separate citations and is not assessed against this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [32] Aloun, 2023, Effect of ursodeoxycholic acid on liver regeneration capacity after living donor hepatectomy: a prospective, randomized, double-blind clinical trial, Eur Rev Med Pharmacol Sci source
- cites [33] Hasan, 2023, Glycine-beta-muricholic acid improves liver fibrosis and gut barrier function by reducing bile acid pool size and hydrophobicity in male Cyp2c70 knockout mice, Cells source
May combine two claims.
PremisecitationThe BA-FXR axis induces detoxification genes in livers of long-lived Little mice rather than CAR and PXR, indicating crosstalk between these nuclear receptors.
“In fact, the BA–FXR axis was shown to induce detoxification genes in the livers of long-lived Little mice rather than CAR and PXR,56 indicative of crosstalk between these nuclear receptors.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [56] Amador-Noguez, 2007, Alterations in xenobiotic metabolism in the long-lived little mice, Aging Cell source
The sections on bile acids as potential mediators and on Car/Pxr mutants support a model in which bile acids acting through Fxr upregulate many detoxification genes in Little mice, while Car and Pxr are not required for most of that upregulation. The paper presents Fxr's role as a proposed mechanism, not a demonstrated induction, and cautions that liver damage could explain the Fxr-mutant result. It does not establish crosstalk among these receptors. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationThere is established sexual dimorphism in liver metabolism.
“Consistent with established sexual dimorphism in liver metabolism64”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [64] Waxman, 2009, Sex differences in the expression of hepatic drug metabolizing enzymes, Mol Pharmacol source
May combine two claims.
Interpretationown dataCAR coordinates metabolic adaptation, particularly by constraining BA homeostasis, and is important for hypermetabolic hepatocytes, which support regeneration by meeting increased metabolic demands.
“Taken together, our data indicate that CAR coordinates metabolic adaptation, particularly by constraining BA homeostasis, and is an important factor for the hypermetabolic hepatocytes, which support regeneration by meeting increased metabolic demands.6”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Chembazhi, 2021, Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver, Genome Res source
The Results section, “Division of labor balances the proliferation and metabolic demands of a regenerating liver” (page unavailable), supports the point that metabolically hyperactive hepatocytes help counteract regeneration-associated deficits in liver function. The cited paper does not establish the attributed role of CAR in coordinating metabolic adaptation or constraining bile-acid homeostasis; the citing sentence presents that as its authors’ own conclusion. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTransient hypoglycemia, hepatic steatosis, and BA overload occur after PHx.
“Consistent with prior reports of transient hypoglycemia,34,35 hepatic steatosis,34,53 and BA overload4,34 occurring after PHx”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [34] Ma, 2025, Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics, Signal Transduct Target Ther source
- cites [35] Huang, 2016, Postponing the hypoglycemic response to partial hepatectomy delays mouse liver regeneration, Am J Pathol source
The section on PH-induced hypoglycemia reports reduced blood glucose after surgery, and the metabolic-response section reports PH-induced elevations in hepatic triglycerides, supporting the hypoglycemia and hepatic fat-accumulation parts of the claim. Our copy does not report bile-acid overload after PHx (searched: bile acid, BA overload). (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [53] Shteyer, 2004, Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice, Hepatology source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPXR can accelerate regeneration.
“PXR can accelerate regeneration,57, 58, 59”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [57] Dai, 2008, Pregnane X receptor is essential for normal progression of liver regeneration, Hepatology source
- cites [58] Jiang, 2019, Pregnane X receptor regulates liver size and liver cell fate by yes-associated protein activation in mice, Hepatology source
- cites [59] Zhang, 2023, PXR triggers YAP-TEAD binding and Sirt2-driven YAP deacetylation and polyubiquitination to promote liver enlargement and regeneration in mice, Pharmacol Res source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationEstrogen can both activate and inhibit CAR signaling depending on the ligand and its context; androgen inhibits CAR transcriptional activity.
“It has been reported that estrogen can both activate and inhibit CAR signaling depending on the ligand and its context,66,67 whereas androgen inhibits CAR transcriptional activity,68”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [66] Makinen, 2003, Dual action of oestrogens on the mouse constitutive androstane receptor, Biochem J source
- cites [67] Hernandez, 2007, The environmental estrogen, nonylphenol, activates the constitutive androstane receptor, Toxicol Sci source
The Results (page not available) show that the environmental estrogen nonylphenol activates CAR. The Discussion (page not available) also describes activation by several environmental estrogens, but our copy does not establish that estrogen inhibits CAR signaling in a different ligand context. The androgen clause is attached to a separate citation and is not judged here. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [68] Kawamoto, 2000, Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene, Mol Endocrinol source
The ‘NR1 Activation by Estrogens’ section reports that estradiol and estrone activate mouse CAR, while several other estrogens have no effect; it does not show an estrogen inhibiting CAR. The ‘Repression of NR1’ section reports dose-dependent repression by androgens. Thus, the androgen claim is supported, but estrogen-dependent inhibition is not established by this paper. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitationc-Myc and CAR are metabolic regulators that modulate expression of genes involved in lipid and glucose homeostasis.
“In addition to their roles in proliferation, both c-Myc and CAR are metabolic regulators that modulate the expression of genes involved in lipid and glucose homeostasis.22,48, 49, 50, 51, 52”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [22] Bhushan, 2021, Yes-associated protein is crucial for constitutive androstane receptor-driven hepatocyte proliferation but not for induction of drug metabolism genes in mice, Hepatology source
The paper’s opening background (indexed under Abstract > Conclusions; page unavailable) calls CAR a regulator of liver energy metabolism, and the Results section on HNF4α reports CAR–HNF4α transcriptional cross-talk. Its discussion of Myc and CAR gene regulation focuses on proliferation; our copy does not establish that both regulate genes involved in lipid and glucose homeostasis. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [48] Yan, 2015, Deciphering the roles of the constitutive androstane receptor in energy metabolism, Acta Pharmacol Sin source
- cites [49] Carroll, 2018, The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis, Front Med source
The “Functional interactions between MYC-MAX and MLXIP-MLX” section reports that MYC stimulates glycolysis and helps regulate genes involved in fatty-acid biosynthesis. The copy does not address CAR as a metabolic regulator; its discussion of glucose- and lipid-responsive gene expression instead concerns MLXIP/MLXIPL-MLX. No page numbers are available in the indexed passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationThe CAR-driven c-Myc-Foxm1 axis has been implicated in promoting hepatocyte proliferation and regeneration in rodents.
“Although the CAR-driven c-Myc–Foxm1 axis has been implicated in promoting hepatocyte proliferation and regeneration in rodents,43,44”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [43] Zheng, 2017, c-MYC-making liver sick: role of c-MYC in hepatic cell function, homeostasis and disease, Genes (Basel) source
Section 3, “Deconstructing c-MYC: Transgenic Models” (page unavailable), reports increased liver regeneration and faster recovery after partial hepatectomy in c-MYC transgenic mice, supporting the rodent proliferation-and-regeneration aspect. The passages found do not link those effects to CAR or Foxm1, so they do not establish the claimed CAR-driven c-Myc–Foxm1 axis. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [44] Baena, 2005, c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver, Proc Natl Acad Sci U S A source
The Results and Discussion (Table 1 section; page not provided) report impaired liver regeneration and reduced proliferation markers after c-Myc deletion in adult mice. This supports a role for c-Myc in regeneration, but our copy does not identify CAR, Foxm1, or a CAR-driven c-Myc–Foxm1 axis (searched: CAR-driven c-Myc Foxm1; constitutive androstane receptor Foxm1). (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataMale CarKO livers show high basal c-Myc expression and maintain this increased expression until 36 hours post-PHx.
“Unexpectedly, male CarKO livers showed high basal c-Myc expression and maintained this increased expression until 36 hours post-PHx (Figure 3A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn CarKO mice, serum BAs increase by approximately 524-fold at 12 hours post-PHx, quickly dampened to control levels by 36 hours in males, but persist at high levels until 72 hours in females.
“Strikingly, increases in serum BAs in CarKO mice were of a much greater magnitude, with a ∼524× increase that was quickly dampened to control levels by 36 hours in males (Figure 5A), but persisted at high levels until 72 hours in females (Figure 5B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn female CarKO livers, peak expression of Foxm1, Ccna2, Ccnb1, Ccnb2, and Cdk1 transcripts is shifted to 72 hours after PHx, whereas Ccnd1 and Ccne1 profiles are comparable to WT female mice.
“However, peak expression of Foxm1, Ccna2, Ccnb1, Ccnb2, and Cdk1 transcripts was shifted right to 72 hours after PHx (Figure 3B–E and H) in female CarKO livers, whereas Ccnd1 and Ccne1 transcript profiles were comparable to WT female mice (Figure 3F and G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt 12 hours post-PHx, BA concentrations are approximately 20-fold higher in serum and 1.8-fold higher in liver in male WT mice compared with 0 hours.
“Compared with 0 hours, at 12 hours post-PHx, we noted BA concentrations to be ∼20× higher in serum, and ∼1.8× higher in the liver in male WT mice (Figure 5A and C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTCPOBOP activates CAR to induce c-Myc, Foxm1, and Cyp2b10 expression in WT mouse liver, and this response is lost in CarKO mice.
“We recapitulated this induction of c-Myc, Foxm1, and the gold-standard metabolic target of CAR, the cytochrome P450, family 2, subfamily b, member 10 (Cyp2b10) gene, after TCPOBOP treatment in the livers of WT mice, a response that is lost in CarKO mice (Figure 1A–C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSerum AST and ALT levels are more pronounced in male CarKO mice than in male WT mice, peaking at 12 hours post-PHx.
“In contrast, serum levels of the liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were more pronounced in male CarKO mice than in WT mice, peaking at 12 hours post-PHx (Figure 2F and G).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBoth male and female WT mice exhibit elevated BA concentrations in serum and liver after PHx, with peak levels at 72 hours.
“Both male and female WT mice exhibited elevated BA concentrations in the serum (Figure 4A) and liver (Figure 4B), with peak levels noted at 72 hours.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWT female mice display a bimodal increase in serum AST and ALT levels at 12 and 72 hours, with female CarKO mice maintaining the 12-hour increase but not at 72 hours.
“In contrast, WT female mice displayed a bimodal increase in serum AST and ALT levels at 12 and 72 hours, with female CarKO mice maintaining the 12-hour increase but not at 72 hours (Figure 2F and G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn male WT mice, expression of c-Myc, Foxm1, Ccna2, Ccnd1, Ccne1, and Cdk1 peaks at 36 hours, not at 12 hours, while Ccnb1 and Ccnb2 peak at 72 hours after PHx.
“The expression of c-Myc, Foxm1, cyclin A2 (Ccna2), Ccnd1, cyclin E1 (Ccne1), and cyclin-dependent kinase 1 (Cdk1) peaked at 36 hours, not at 12 hours, when Car transcript levels were high post-PHx in male WT mice, whereas cyclin B1 (Ccnb1) and cyclin B2 (Ccnb2) peaked at 72 hours after PHx in male WT mice (Figure 3A–H).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataFemale WT mice have BA concentrations approximately 12-fold higher in serum and 2.4-fold higher in liver than male WT mice.
“Of note, female WT mice BA concentrations were ∼12× higher in serum and ∼2.4× higher in the liver than those of male mice (Figure 4A and B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCarKO and WT mice show no noticeable differences in body weight, liver weight, or BrdU incorporation after PHx, regardless of sex.
“However, we did not observe any noticeable differences in body weight (Figure 2D), liver weight (Figure 2E), or 5-bromo-2'-deoxyuridine (BrdU) incorporation (Figure 2B and C) between CarKO and WT mice, regardless of sex.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFemale WT livers show two peaks of c-Myc at 12 and 72 hours, whereas female CarKO livers display a robust increase in c-Myc transcript at 12 hours but not at 72 hours after PHx.
“Female WT livers showed 2 peaks of c-Myc at 12 and 72 hours, whereas female CarKO livers displayed a robust increase in c-Myc transcript at 12 hours but not at 72 hours after PHx (Figure 3A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBoth unconjugated and taurine-conjugated BAs are increased in the serum and liver of male CarKO mice at 12 hours post-PHx.
“Both unconjugated and taurine-conjugated BAs were increased in the serum and liver of male CarKO mice at 12 hours (Figure 5A and C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCar transcript expression is dynamically regulated during regeneration, peaking at 12 hours and falling below basal levels by 72 hours post-partial hepatectomy.
“Car transcript expression is dynamically regulated during regeneration, peaking at 12 hours and plummeting below basal levels by 72 hours post-partial hepatectomy.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataFemale CarKO mice exhibit a left shift of the BA peak, with an acute early rise in systemic and hepatic BA levels at 12 or 36 hours rather than 72 hours.
“Also, female CarKO mice exhibited a left shift of the BA peak, indicating an acute early rise in systemic and hepatic BA levels at 12 or 36 hours, rather than 72 hours (Figure 4A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn female CarKO mice, Cyp7a1 and Cyp8b1 mRNA levels plummet at 12 hours and rebound at 72 hours after PHx.
“Similarly, mRNA levels of Cyp7a1 and Cyp8b1 plummeted at 12 hours and rebounded at 72 hours in female CarKO mice (Figure 7A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCompared with male WT serum, CarKO serum shows increased proportions of hydrophobic DCA and lower hydrophilic MCA at 0 hours, which is increased at 36 and 72 hours post-PHx.
“Compared with male WT serum, CarKO serum showed increased proportions of hydrophobic deoxycholic acid (DCA) and lower hydrophilic muricholic acid (MCA) at 0 hours, which was increased at 36 and 72 hours post-PHx (Figure 4C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn CarKO livers, CHR-induced increases in BA synthesis genes (Cyp7a1 and Cyp8b1) are more pronounced, whereas CHR-induced decreases in BA export and detox genes (Bsep and Cyp2b10) are dampened.
“Notably in CarKO livers, CHR-induced increases in BA synthesis genes (Cyp7a1 and Cyp8b1) were more pronounced (Figure 10A), whereas CHR-induced decreases in BA export and detox genes (Bsep and Cyp2b10) were dampened (Figure 10B and C).”
Quote in the paperSubstantial claim- Rests on an assumption: Cholestyramine's effect on hepatocyte proliferation is mediated specifically by reducing bile acid levels, not by other effects of the drug.
May combine two claims.
Findingown dataDetoxification genes Cyp2b10, Sult2a1, and/or Cyp3a11 decrease at 12 hours in male and female WT mice after PHx.
“Detoxification genes Cyp2b10, sulfotransferase family 2a member 1 (Sult2a1), and/or cytochrome P450, family 3, subfamily a, member 11 (Cyp3a11) decreased at the 12-hour time point in male and female WT mice after PHx (Figure 7C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCHR-fed WT and CarKO mice exhibit elevated mRNA levels of BA synthesis genes and reduced expression of BA export and detoxification genes compared with chow-fed mice, to compensate for a reduced BA pool.
“To compensate for a reduced BA pool,5,39,40 we observed that CHR-fed WT and CarKO mice exhibited elevated mRNA levels of BA synthesis genes and reduced expression of BA export and detoxification genes compared with chow-fed mice (Figure 10A–C).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science source
- cites [39] Chiang, 1990, Regulation of cholesterol 7 alpha-hydroxylase in the liver. Purification of cholesterol 7 alpha-hydroxylase and the immunochemical evidence for the induction of cholesterol 7 alpha-hydroxylase by cholestyramine and circadian rhythm, J Biol Chem source
- cites [40] Qiu, 2017, Cholestyramine alters bile acid amounts and the expression of cholesterol-related genes in rabbit intestinal and hepatic tissues, J Dig Dis source
May combine two claims.
Findingown dataIn male WT mice, Cyp8b1 and Cyp27a1 levels are maintained lower throughout the 12- to 72-hour proliferative period and restored at 96 hours after PHx.
“cytochrome P450, family 8, subfamily b, member 1 (Cyp8b1) and cytochrome P450, family 27, subfamily a, member 1 (Cyp27a1) levels, on the other hand, were maintained lower throughout the 12- to 72-hour proliferative period, but their expression was restored at the termination phase at 96 hours (Figure 7A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDespite higher basal levels in CarKO female mice, the expression profile of BA transporters post-PHx is identical to WT female mice, and BA transporter gene expression in CarKO male mice is indistinguishable from WT male mice.
“Despite higher basal levels in CarKO female mice, the expression profile of these transporters post-PHx was identical to that of WT female mice (Figure 7B), and similarly, BA transporter gene expression in CarKO male mice was indistinguishable from that of WT male mice (Figure 7B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAlthough Cyp2b10 mRNA remains poorly expressed in the absence of Car at 0, 36, 72, and 96 hours, modulations in Cyp3a11 and Sult2a1 transcript levels post-PHx are maintained.
“Although Cyp2b10 mRNA remained poorly expressed in the absence of Car at 0, 36, 72, and 96 hours, modulations in Cyp3a11 and Sult2a1 transcript levels post-PHx were maintained (Figure 7C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCHR dampens expression of Foxm1 and cell-cycle genes mainly in CarKO livers, indicating the BA spike may facilitate regeneration in CarKO mice.
“Importantly, CHR dampened the expression of Foxm1 and cell-cycle genes mainly in CarKO livers (Figure 9B–H), indicating that the BA spike may facilitate regeneration in CarKO mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Cholestyramine's effect on hepatocyte proliferation is mediated specifically by reducing bile acid levels, not by other effects of the drug.
May combine two claims.
Findingown dataDespite comparable BA concentrations, CHR-fed CarKO mice display higher proportions of chenodeoxycholic acid and MCA along with lower levels of DCA compared with CHR-fed WT mice.
“Despite comparable BA concentrations, CHR-fed CarKO mice displayed higher proportions of chenodeoxycholic acid and MCA along with lower levels of DCA compared with CHR-fed WT mice (Figure 8C and D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCHR reduced ileal BA levels and Fgf15 mRNA in both WT and CarKO mice.
“As expected, CHR reduced the levels of ileal BAs and Fgf15 mRNA in both WT and CarKO mice (Figure 11A and C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBA export genes Bsep and Mrp2/3/4 exhibit a general reduction after PHx in male WT livers, except for a transient increase in Mrp2 at 36 hours and a 50% derepression of Bsep transcript by 72 hours.
“We also examined and found that BA export genes bile salt export pump (Bsep) and multidrug resistance protein 2/3/4 (Mrp2/3/4) exhibited a general reduction after PHx in male WT livers, except for a transient increase in Mrp2 at 36 hours and a 50% derepression of Bsep transcript by 72 hours (Figure 7B), suggesting that the reduced export can also contribute to the initial rise seen in hepatic BAs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPHx-induced hypoglycemia occurs at 12 hours after PHx in WT mice and is more pronounced in CarKO mice.
“So, we next assessed blood glucose levels in male CarKO and WT mice after PHx and, as expected, observed PHx-induced hypoglycemia at 12 hours after PHx in WT mice, which was more pronounced in CarKO mice (Figure 6).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataQuiescent adult hepatocytes display robust expression of most CAR target genes, with subsets showing temporal changes during regeneration stages.
“Moreover, quiescent adult hepatocytes displayed robust expression of most CAR targets; however, subsets of these targets exhibited temporal alterations in their expression during the initiation, progression, and termination stages (Figure 12B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn male mice, detoxification gene expression rebounds to higher levels at 36 hours and then gradually decreases at 72 and 96 hours, whereas in female mice, it gradually increases between 72 and 96 hours after PHx.
“In male mice, their expression rebounded to higher levels at 36 hours and then gradually decreased at 72 and 96 hours (Figure 7C), whereas in female mice, it gradually increased between 72 and 96 hours (Figure 7C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCholestyramine feeding decreases BA levels in WT mice (approximately 40% reduction in serum, 70% reduction in liver) and CarKO mice (approximately 70% reduction in serum, 80% reduction in liver) at 36 hours after PHx.
“As anticipated, CHR led to a decrease in BA levels in WT (∼40% reduction in the serum, ∼70% reduction in the liver) and CarKO (∼70% reduction in the serum, ∼80% reduction in the liver) mice at 36 hours after PHx (Figure 8A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn female WT mice, expression of BA synthesis genes is lowest at 72 hours post-PHx, indicating a temporal shift in regulation of BA synthesis when Car is deleted in female livers.
“But in female WT mice, the expression of these genes was lowest at 72 hours post-PHx (Figure 7A), indicating a temporal shift in the regulation of BA synthesis during liver regeneration when Car is deleted in female livers.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn male WT mice, Cyp7a1 expression is downregulated at 36 hours and rebounds at 72 hours after PHx.
“In male WT mice, the expression of the BA synthesis gene cytochrome P450, family 7, subfamily a, member 1 (Cyp7a1) was downregulated at 36 hours, which rebounded at 72 hours (Figure 7A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCar deletion leads to a rapid drop in Cyp7a1 transcript expression, whereas decreases in Cyp8b1 and Cyp27a1 are similar to WT mice after PHx.
“Car deletion led to a rapid drop in Cyp7a1 transcript expression, whereas the decreases in Cyp8b1 and Cyp27a1 were similar to those of the WT mice (Figure 7A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe drastic increase in serum BA levels at 12 hours post-PHx upon loss of Car is not reflected in hepatic levels, which are approximately 4-fold higher in male mice and 2-fold higher in female mice.
“However, the drastic increase in serum BA levels seen at 12 hours post-PHx upon loss of Car is not reflected in hepatic levels, which were ∼4× higher in male mice and ∼2× higher in female mice (Figure 5A–D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHepatic BA composition post-PHx in female CarKO livers is comparable to WT livers, but serum levels, although elevated, show a hydrophilic BA composition with a higher MCA/CA ratio and reduction in DCA compared with WT mice.
“On the other hand, hepatic BA composition post-PHx in female CarKO livers was comparable to WT livers (Figure 4F), but serum levels, although elevated, showed a hydrophilic BA composition with a higher MCA/CA ratio and reduction in DCA levels compared with WT mice (Figure 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn male WT mice after PHx, Car transcript expression in hepatocytes is highest at 24 h, lower at 48 h, and dissipated at 96 h.
“Similar to the quantitative polymerase chain reaction results (Figure 2A), Car transcript was most prominent at 24 hours post-PHx, followed by 48 hours post-PHx, and dissipated at 96 hours post-PHx (Figure 12A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn CarKO livers compared with WT, Shp transcript levels did not reach significance; Cyp7a1 and Cyp8b1 transcripts were not reduced; Bsep mRNA was induced.
“Compared with WT livers, Shp transcript levels did not reach significance in CarKO livers (Figure 13A), neither Cyp7a1 nor Cyp8b1 transcripts were reduced (Figure 13B and C), and Bsep mRNA was rather induced in CarKO mice (Figure 13D)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDeletion of CAR led to more hypoglycemia and a dramatic BA surge during the early phases of regeneration in CarKO mice.
“the deletion of CAR led to more hypoglycemia and a dramatic BA surge during the early phases of regeneration in CarKO mice (Figures 4A and B and 6).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn CarKO livers, both magnitude and composition of the bile acid pool are altered.
“Importantly, both the magnitude and composition of the BA pool are altered in CarKO livers.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn male CarKO mice, the BA pool becomes more hydrophobic, reflected by reduced MCA/CA ratio, consistent with higher serum AST and ALT.
“The BA pool becomes more hydrophobic, as reflected by a reduced MCA/CA ratio that is in line with higher serum AST and ALT levels in male CarKO mice (Figures 2F and G and 4E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCHR selectively dampens pro-proliferation and cell-cycle gene expression, particularly in CarKO livers, while regeneration in WT mice proceeds with only a modest delay.
“Instead, CHR selectively dampens pro-proliferation and cell-cycle gene expression, particularly in CarKO livers, whereas regeneration in WT mice proceeds with only a modest delay (Figures 8E and F and 9A–H).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationBile acids are transiently elevated following PHx and promote liver regeneration, whereas CAR prevents BA hepatotoxicity.
“It is known that BAs are transiently elevated following PHx and promote liver regeneration,3,4 whereas CAR has been shown to prevent BA hepatotoxicity.10”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [3] Doignon, 2011, Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis, J Hepatol source
- cites [4] Pean, 2013, The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice, Hepatology source
- cites [10] Zhang, 2004, The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity, J Biol Chem source
May combine two claims.
Interpretationown dataIn the absence of Car, BA accumulation peaks at 12 hours post-PHx and is inflated during liver regeneration.
“Thus, our findings demonstrate that in the absence of Car, BA accumulation peaks at 12 hours post-PHx and is inflated during liver regeneration.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationFollowing two-thirds PHx, the abrupt loss of liver mass is overcome by coordinated hepatocyte proliferation and metabolic adaptation through a division of labor among remaining hepatocytes.
“Following two-thirds partial hepatectomy (PHx), a well-established model of liver regeneration, the abrupt loss of liver mass is overcome by coordinated hepatocyte proliferation and metabolic adaptation through a division of labor among the remaining hepatocytes.2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Caldez, 2018, Metabolic remodeling during liver regeneration, Dev Cell source
May combine two claims.
Interpretationown dataDownregulation of Cyp2b10, Sult2a1, and Cyp3a11 corresponds to the time point when Car transcript is induced at 12 hours post-PHx in WT livers, indicating CAR-mediated regulation may be focused on endogenous metabolism, such as BAs.
“It is intriguing to note that the downregulation of these 3 detox genes corresponds to a time point when the Car transcript is induced at 12 hours post-PHx in WT livers, indicating that CAR-mediated regulation may be focused on endogenous metabolism, such as BAs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningSuch a mechanism could be functional in CarKO mice to protect hepatocytes as they recover from the PHx-induced BA surge.
“We posit that such a mechanism could be functional in CarKO mice to protect hepatocytes as they recover from this PHx-induced BA surge.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCAR-mediated signaling maintains and stimulates metabolic functions, rather than promoting proliferation, during liver regeneration.
“This intriguing result reveals a paradigm-shifting role for CAR-mediated signaling in maintaining and stimulating metabolic functions, rather than promoting proliferation, during liver regeneration.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataTaurine-conjugated BAs are a significant fraction of the total BA pool in mice.
“Nonetheless, these data are consistent with taurine-conjugated BAs being a significant fraction of the total BA pool in mice.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCAR controls BA levels and composition in both systemic circulation and the liver.
“These results reveal a role of CAR in controlling BA levels and composition in both systemic circulation and the liver.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElevated BAs can activate FXR, PXR, and CAR.
“Elevated BAs can activate the FXR, pregnane X receptor (PXR), and CAR.54,55”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [54] Wagner, 2005, CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice, Hepatology source
- cites [55] Guo, 2003, Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity, J Biol Chem source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningA limitation of the BA analysis is that d4-TMCA was used as internal standards for all MCA species, so α-, β-, and ω-isomers of MCA or TMCA cannot be distinguished.
“A limitation of the BA analysis is that d4-TMCA was used as internal standards for all the MCA species, and so we are unable to distinguish between α-, β-, and ω-isomers of MCA or TMCA.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Loss-of-function studies of CAR in liver regeneration are sparse, and the temporal dynamics and metabolic functions of CAR during regeneration are not yet elucidated.
“Although pharmacological activation of CAR has been demonstrated to stimulate liver regeneration,20,24 loss of function studies remain sparse. Existing reports suggest impaired regeneration in Car knockout (CarKO) mice post-PHx,5,24 but the temporal dynamics and metabolic functions of CAR during regeneration are yet to be elucidated.”
The paper relies on this without support.
Cholestyramine's effect on hepatocyte proliferation is mediated specifically by reducing bile acid levels, not by other effects of the drug.
“It is pertinent to note that CHR-fed WT mice also showed a reduced number of BrdU-positive nuclei compared with chow-fed WT mice (Figure 8E and F), validating a role for the BA spike in liver regeneration, consistent with previous findings.5,36”
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.
Female CarKO serum MCA/CA ratio is described as higher, but Table 2 shows it lower
MinorThe text says female CarKO serum has a higher MCA/CA ratio than WT serum. At 36 hours in Table 2, the ratio is about 1.28 in CarKO mice (254,796.1/199,624.7) versus 2.00 in WT mice (22,732.3/11,353.4); the table also shows a lower CarKO ratio at 12 and 72 hours.
“but serum levels, although elevated, showed a hydrophilic BA composition with a higher MCA/CA ratio and reduction in DCA levels compared with WT mice (Figure 4D).”
“| | PHx 36 hours | PHx 36 hours | PHx 72 hours | PHx 72 hours | | CA | 11,353.4 ± 2136.9 | 199,624.7 ± 22,833.7 | 52,231.0 ± 1978.0 | 51,479.6 ± 24,470.9 | | CDCA | 647.8 ± 203.5 | 2760.1 ± 416.2 | 1836.6 ± 747.0 | 1023.4 ± 368.3 | | UDCA | 317.3 ± 58.7 | 4396.8 ± 2237.8 | 1127.7 ± 187.0 | 847.5 ± 316.3 | | MCA | 22,732.3 ± 2874.7 | 254,796.1 ± 34,938.2 | 318,900.6 ± 88,716.3 | 133,686.1 ± 62,587.5 |”
Figure 9 caption disagrees on whether female mice were studied
MinorThe Figure 9 caption first identifies the CHR experiment as involving male mice, then describes its plotted measurements as coming from male and female mice.
“Male CarKO and WT mice were fed with CHR 1 week prior to PHx, and the expression of pro-proliferation and cell-cycle genes was determined at 36 hours post-PHx.”
“(A–H) mRNA levels of genes regulating cell proliferation in the livers of male and female WT and CarKO mice at 36 hours after PHx on normal chow (n = 5–7 mice) or CHR diet (n = 4 mice).”
Female liver injury markers are called comparable despite a reported difference at 72 hours
MinorThe discussion describes female CarKO liver injury markers as comparable to WT controls, while the results state that WT females had a second AST and ALT increase at 72 hours that CarKO females did not.
“In contrast, female CarKO mice exhibit BA profiles and liver injury markers comparable to WT controls (Figures 2F and G and 4D and F), revealing a sex-specific role for CAR in maintaining BA homeostasis during regeneration.”
“In contrast, WT female mice displayed a bimodal increase in serum AST and ALT levels at 12 and 72 hours, with female CarKO mice maintaining the 12-hour increase but not at 72 hours (Figure 2F and G).”
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Abe, T., Amaike, Y., Shizu, R., Takahashi, M., Kano, M., Hosaka, T., Sasaki, T., Kodama, S., Matsuzawa, A., & Yoshinari, K. (2018) · Toxicological Sciences · doi:10.1093/toxsci/kfy149 · Cited by 36 · see citing works
Ganzenberg, K., Singh, Y., & Braeuning, A. (2013) · Toxicology · doi:10.1016/j.tox.2013.03.019 · Cited by 29 · see citing works
Kim, K. H., Choi, J. M., Li, F., Dong, B., Wooton‐Kee, C. R., Arizpe, A., Anakk, S., Jung, S. Y., Hartig, S. M., & Moore, D. D. (2019) · Hepatology Communications · doi:10.1002/hep4.1274 · Cited by 27 · see citing works
Self-citationLickteig, A. J., Csanaky, I. L., Pratt-Hyatt, M., & Klaassen, C. D. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw054 · Cited by 26 · cited 1× · see citing works
“Consistent with previous reports, 12,30 we observed sex differences in BA composition (Figure 4 C– lower hydrophilic muricholic acid (MCA) at 0 hours, which was increased at 36 and 72 hours post-PHx (Figure 4 C ).”
Dong, X., Zhao, H., Ma, X., & Wang, S. (2010) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-010-0110-8 · Cited by 20 · see citing works
Cross-species comparison of CAR-mediated procarcinogenic key events in a 3D liver microtissue model
Plummer, S., Beaumont, B., Wallace, S., Ball, G., Wright, J., McInnes, L., Currie, R., Peffer, R., & Cowie, D. (2019) · Toxicology Reports · doi:10.1016/j.toxrep.2019.09.010 · Cited by 20 · see citing works
Bhushan, B., Molina, L., Koral, K., Stoops, J. W., Mars, W. M., Banerjee, S., Orr, A., Paranjpe, S., Monga, S. P., Locker, J., et al. (2021) · Hepatology · doi:10.1002/hep.31521 · Cited by 20 · see citing works
Hasan, M. N., Chen, J., Wang, H., Du, Y., Clayton, Y. D., Gu, L., & Li, T. (2023) · Cells · doi:10.3390/cells12101371 · Cited by 16 · see citing works
Mathur, B., Arif, W., Patton, M. E., Faiyaz, R., Liu, J., Yeh, J., Harpavat, S., Schoonjans, K., Kalsotra, A., Wheatley, A. M., et al. (2020) · JHEP Reports · doi:10.1016/j.jhepr.2020.100140 · Cited by 14 · see citing works
Self-citationProteomic analysis of hepatic effects of phenobarbital in mice with humanized liver
Sprenger, H., Rasinger, J. D., Hammer, H., Naboulsi, W., Zabinsky, E., Planatscher, H., Schwarz, M., Poetz, O., & Braeuning, A. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03338-7 · Cited by 12 · see citing works
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Melanchole: the dark side of bile acids and its cellular consequences
Zhou, W., & Anakk, S. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.003 · Cited by 6 · see citing works
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Self-citationThe benevolent bile: bile acids as stimulants of liver regeneration
Bhushan, B., & Apte, U. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.004 · Cited by 4 · see citing works
Rebuttal to: the benevolent bile: bile acids as stimulants of liver regeneration
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- Authors
- Zhou, W., Chembazhi, U. V., Huang, J., Bangru, S., Dean, A. E., Asokakumar, A., Kalsotra, A., Rudnick, D. A., & Anakk, S.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- St. Louis Children's Hospital (US)
- ORCID
- Venue
- Cellular and Molecular Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2026
- Volume
- 20
- Issue
- 11
- Pages
- 101858
- ISSN
- 2352-345X (ISSN-L)
- PMC
- PMC13629341
- OpenAlex
- W7202249994
- Semantic Scholar
- 64913d9be96789cb44d87fca262d30605498298d
- Cited by
- 0
- References
- 73
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Cancer Center at Illinois
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK113080)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- constitutive androstane receptor, liver regeneration, partial hepatectomy, bile acid homeostasis, bile acid metabolism, hepatocyte proliferation, cholestyramine, single-cell RNA sequencing, xenobiotic metabolism
- MeSH terms
- Constitutive Androstane Receptor, Animals, Bile Acids and Salts, Gene Expression Regulation, Hepatectomy, Homeostasis, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Hepatocytes, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-22.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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