Activation of LXRs prevents bile acid toxicity and cholestasis in female mice

Uppal, Hirdesh; Saini, S. S.; Moschetta, Antonio; Mu, Ying; Zhou, Jie; Gong, Haibiao; Zhai, Yonggong; Ren, Shuling; Michalopoulos, George K.; Mangelsdorf, David J.; Xie, Wen

doi:10.1002/hep.21494

Cited by 123 publications

(122 citation statements)

References 60 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…Sult2a1/2 was also increased in LCA-treated CAR-null mice, which is consistent with hydroxysteroid sulfotransferase-mediated LCA sulfation as a major pathway for protection against LCA-induced liver damage (Kitada et al, 2003). Because LXR has been associated with increased expression of Sult2a, it is likely that the increase observed in CAR-null mice was a result of LXR (Uppal et al, 2007).…”

Section: Car Activation Alters Bile Acid Biosynthesissupporting

confidence: 70%

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

et al. 2009

View full text Add to dashboard Cite

ABSTRACT:Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB-and TCPOBOP-pretreated WT mice correlated with hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the hepatoprotection observed during LCA-induced liver injury.

show abstract

Section: Car Activation Alters Bile Acid Biosynthesissupporting

confidence: 70%

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

et al. 2009

View full text Add to dashboard Cite

show abstract

“…It has been established that hepatic expression of Cyp7b1 is greater in male mice, whereas that of Cyp39a1 is greater in females [21,22]. This pattern appears to be potentiated by TSA treatment, at least under acute conditions, suggesting that epigenetic mechanisms may be a general regulator of sexually dimorphic cytochrome P450 expression (results not shown).…”

Section: Cyp7b1mentioning

confidence: 91%

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors

Shafaati

O’Driscoll

Björkhem

et al. 2009

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Keywords:24S-hydroxycholesterol CYP46A1 CYP39A1 Epigentics Histone deacetylase inhibitor Oxysterol Brain cholesterol a b s t r a c tThe mechanistic basis for the tissue specific expression of cholesterol elimination pathways is poorly understood. To gain additional insight into this phenomenon we considered it of interest to investigate if epigenetic mechanisms are involved in the regulation of the brain-specific enzyme cholesterol 24-hydroxylase (CYP46A1), a key regulator of brain cholesterol elimination. We demonstrated a marked time-dependent derepression of the expression of CYP46A1, in response to treatment with the potent histone deacetylase (HDAC) inhibitor Trichostatin A. The pattern of expression of the genes in the genomic region surrounding CYP46A1 was found to be diametrically opposite in brain and liver. Intraperitoneal injection of HDAC inhibitors in mice led to a significant derepression of hepatic Cyp46a1 mRNA expression and tissue specific changes in Hmgcr and Cyp39a1 mRNA expression. These results are discussed in the context of the phenomenology of tissue specific cholesterol balance.Ó 2008 Elsevier Inc. All rights reserved.Although all nucleated cells are capable of cholesterol synthesis, their ability to do so varies over several orders of magnitude. In the adult state most organisms have established a certain level of tissue specialisation [1]. The rate of cholesterol synthesis and the cholesterol content of a given tissue are not necessarily directly related, e.g. the adult brain contains more than 25% of whole body cholesterol but turns over only 0.03% of its cholesterol content each day. This turnover is much lower than the developing brain [1] where cholesterol rich myelin is being formed. The slow turnover of brain cholesterol is in marked contrast to that in most other organs [1,2]. The mechanistic basis for these differences is unknown, although they are probably a result of the functional isolation of brain and blood cholesterol [3][4][5].According to current concepts, the synthesis and elimination of cholesterol in the adult brain is compartmentalised-astroglial cells are believed to be responsible for the majority of synthesis in the adult brain while they contribute relatively little to brain elimination. The neuron specific cytochrome P450 cholesterol 24-hydroxylase (CYP46A1) is responsible for the elimination of about two thirds of the cholesterol synthesised by the brain [6,7]. Recently it was shown that deletion of this gene led to a reduction in the rate of brain cholesterol synthesis while the level of brain cholesterol was maintained [8]. Due to the importance of this enzyme for brain cholesterol balance we have previously investigated its transcriptional regulation [9], with an expectation that a gene so important for brain cholesterol balance would be subject to complex mechanisms of regulation. Surprisingly we found the opposite-expression of CYP46A1 was insensitive to mechanisms known to regulate the key genes in cholesterol synthesis and elimination, HMGCR and CYP7A1,...

show abstract

“…The creation of PXR(Ϫ/Ϫ) (Xie et al, 2000a), CAR(Ϫ/Ϫ) (Wei et al, 20000), PXR/CAR double knockout (PC DKO) (Saini et al, 2004), LXR DKO (Peet et al, 1998), VP-CAR transgenic (Saini et al, 2004), and fatty acid binding protein-VP-LXR␣ transgenic (Uppal et al, 2007) mice has been described previously. All transgenic and their wild-type control mice were maintained in a mixed background of C57BL/6J and 129/SvJ, except for the wild-type mice used in Fig.…”

Section: Methodsmentioning

confidence: 99%

A Functional Cross-Talk between Liver X Receptor-α and Constitutive Androstane Receptor Links Lipogenesis and Xenobiotic Responses

Zhai

Wada²,

Zhang³

et al. 2010

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

The liver X receptor (LXR) and constitutive androstane receptor (CAR) are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. Here, we show that LXR␣ and CAR are functionally related in vivo. Loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation, whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced lipogenesis. On the other hand, a combined loss of LXR ␣ and ␤ increased the basal expression of xenobiotic CAR target genes, whereas activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants. The mutual suppression between LXR␣ and CAR was also observed in cell culture and reporter gene assays. LXR␣, like CAR, exhibited constitutive activity in the absence of an exogenously added ligand by recruiting nuclear receptor coactivators. Interestingly, although CAR competed with LXR␣ for coactivators, the constitutive activity and recruitment of coactivators was not required for CAR to suppress the activity of LXR␣. In vivo chromatin immunoprecipitation assay showed that cotreatment of a CAR agonist compromised the LXR agonist responsive recruitment of LXR␣ to Srebp-1c, whereas an LXR agonist inhibited the CAR agonist-responsive recruitment of CAR to Cyp2b10. In conclusion, our results have revealed dual functions of LXR␣ and CAR in lipogenesis and xenobiotic responses, establishing a unique role of these two receptors in integrating xenobiotic and endobiotic homeostasis.

show abstract

Activation of LXRs prevents bile acid toxicity and cholestasis in female mice

Cited by 123 publications

References 60 publications

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice

Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors

A Functional Cross-Talk between Liver X Receptor-α and Constitutive Androstane Receptor Links Lipogenesis and Xenobiotic Responses

Contact Info

Product

Resources

About