Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α

Wang, Cheng; Zhang, Fengxiao; Wang, Lin; Zhang, Yanqing; Li, Xiangrao; Huang, Kun; Du, Meng; Liu, Fangmei; Huang, Shizheng; Guan, Youfei; Huang, Dan; Huang, Kai

doi:10.1128/mcb.00160-13

Cited by 33 publications

(29 citation statements)

References 35 publications

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“…In fact, PARP-1 has been shown to be a transcriptional coregulator for a number of nuclear receptors including thyroid hormone receptor, estrogen receptor ␣, retinoic acid receptor, and farnesoid X receptor (42,43,46). Here we report that PARP-1 interacts with both LXR␣ and LXR␤, and functions as a gene-specific corepressor of LXR-mediated gene expression.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

Shrestha

Hussein

Savas

et al. 2016

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

Shrestha

Hussein

Savas

et al. 2016

Journal of Biological Chemistry

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“…Increasing evidence suggests that FXR may play an important role in liver detoxification, regeneration, and carcinogenesis (6,32,33). FXR has also been found to be expressed in many "nonclassical" bile salt target tissues, including the vasculature and macrophages, where FXR influences vascular tension and regulates the unloading of cholesterol from foam cells, respectively (34).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts.water homeostasis | bile acid receptor T he farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, with the typical functional domains including the DNA binding domain and the ligand binding domain. Upon binding to its ligands, FXR forms a heterodimer with another nuclear receptor, retinoid X receptor, whereupon the receptor dimer binds to the FXR response element (FXRE) located in the promoter regions of FXR target genes, thereby regulating the transcription of these genes (1-3). The single FXR gene gives rise to two isoforms, designated as FXRα and FXRβ, as a result of alternative use of the promoters (4). In addition, each FXR isoform has two variants (FXRα1/FXRβ1 and FXRα2/ β2), depending on the presence or absence of an insert of four amino acids (MYTG) immediately adjacent to the DNA binding domain in the hinge domain (5). Because FXRβ constitutes a pseudogene in humans and primates, all recent studies focus on FXRα (6).FXR is highly expressed in the liver and intestine, where it functions as an intracellular sensor of bile acids and is required for the negative feedback regulation of bile acid biosynthesis and its enterohepatic cycle (7,8). Most recently FXR has been found to be involved in the regulation of adrenal and vascular function, as well as hepatic glucose and lipid metabolism, which suggests an important role for FXR in many tissues beyond the hepatointestinal system (9-12). Among most tissues tested, the kidney exhibits the highest expression levels (13). However, the role of FXR in the kidney remains largely unknown. It has been previously reported that FXR may negatively regulate sterol regulatory element-binding protei...

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“…These findings are in line with the literature reporting that CsA induces oxidative stress, unfolded protein response, and inflammation [ 11 , 19 , 32 ]. However, the lack of major differences in response of WT-PCLS and FXRKO-PCLS to CsA seems to be in contrast to findings of Wang and colleagues who demonstrated that Fxr-deficiency in Fxr-KO mice and human hepatocytes have significantly increased hepatotoxicity upon exposure to other inducers of oxidative stress represented by carbon tetrachloride (CCl 4 ) and hydrogen peroxide (H 2 O 2) respectively [ 33 ]. It was shown that oxidative stress induced by CCl 4 or H 2 O 2 inhibit the binding of FXR to FXRE by increased poly (ADP-ribosyl) ation of FXR catalysed by poly (ADP-ribose) polymerase 1 (PARP1), which alters FXR conformation leading to dissociation of FXR from FXRE and thereby suppresses expression of FXR target genes involved in hepatoprotection [ 33 ].…”

Section: Discussionmentioning

confidence: 92%

“…However, the lack of major differences in response of WT-PCLS and FXRKO-PCLS to CsA seems to be in contrast to findings of Wang and colleagues who demonstrated that Fxr-deficiency in Fxr-KO mice and human hepatocytes have significantly increased hepatotoxicity upon exposure to other inducers of oxidative stress represented by carbon tetrachloride (CCl 4 ) and hydrogen peroxide (H 2 O 2) respectively [ 33 ]. It was shown that oxidative stress induced by CCl 4 or H 2 O 2 inhibit the binding of FXR to FXRE by increased poly (ADP-ribosyl) ation of FXR catalysed by poly (ADP-ribose) polymerase 1 (PARP1), which alters FXR conformation leading to dissociation of FXR from FXRE and thereby suppresses expression of FXR target genes involved in hepatoprotection [ 33 ]. The lack of differences between FXRKO-PCLS and WT-PCLS with respect to regulation of stress response pathways and hepatotoxic effects in our study and the observations of Wang and colleagues could be explained by (i) differences in the mechanism of action between CsA and CCl 4 /H 2 O 2 and/or (ii) model-dependent differences.…”

Section: Discussionmentioning

confidence: 92%

Cyclosporin A induced toxicity in mouse liver slices is only slightly aggravated by Fxr-deficiency and co-occurs with upregulation of pro-inflammatory genes and downregulation of genes involved in mitochondrial functions

2015

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BackgroundThe transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR.MethodsTo test this hypothesis, PCLS obtained from livers of wild type mice (WT-PCLS) and Fxr-knockout mice (FXRKO-PCLS) were treated with 40 μM CsA for 24 h and 48 h. ATP and histological assays were applied to assess the viability of PCLS. DNA microarrays combined with bioinformatics analysis were used to identify genes and processes that were affected by CsA in WT-PCLS and/or FXRKO-PCLS. In addition, WT-PCLS and FXRKO-PCLS were exposed to the endogenous FXR ligand chenodeoxycholic acid (CDCA) and subjected to q-PCR to determine whether subsets of known FXR-targets and the identified genes were regulated upon FXR activation in an FXR-dependent manner.ResultsNo difference in viability was observed between WT-PCLS and FXRKO-PCLS upon CsA treatment. Transcriptomics data analysis revealed that CsA significantly upregulated stress-response and inflammation and significantly downregulated processes involved in lipid and glucose metabolism in WT-PCLS and FXRKO-PCLS. However, only in FXRKO-PCLS, CsA upregulated additional pro-inflammatory genes and downregulated genes related to mitochondrial functions. Furthermore, only in WT-PCLS, CDCA upregulated a subset of known FXR-target genes as well as the regulator of inflammation and mitochondrial functions peroxisome proliferator- activated receptor delta (Ppar delta).ConclusionsAlthough FXR governs energy metabolism, no major differences in response to CsA could be observed between WT-PCLS and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism. This finding indicates that CsA does not directly affect FXR functions in relation to the above mentioned processes. However, the more pronounced induction of pro-inflammatory genes and the downregulation of genes involved in mitochondrial functions only in FXRKO-PCLS suggest that FXR deficiency aggravates CsA-induced inflammation and impairs mitochondrial functions. Therefore, FXR can exert its hepatoprotective functions by controlling inflammation and mitochondrial functions, possibly involving an FXR-PPAR delta cross-talk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2054-7) contains supplementary material, which is available to authorized users.

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Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α

Cited by 33 publications

References 35 publications

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Cyclosporin A induced toxicity in mouse liver slices is only slightly aggravated by Fxr-deficiency and co-occurs with upregulation of pro-inflammatory genes and downregulation of genes involved in mitochondrial functions

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