Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid–induced liver hypertrophy†

Xing, Xin; Burgermeister, Elke; Geisler, Fabian; Einwächter, Henrik; Fan, Li; Hiber, Michaela; Rauser, Sandra; Walch, Axel; Röcken, Christoph; Ebeling, Martin; Wright, Matthew B.; Schmid, Roland M.; Ebert, Matthias

doi:10.1002/hep.22712

Cited by 28 publications

(17 citation statements)

References 54 publications

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“…Antibody and hematoxylin-eosin (H&E) stainings were performed as described previously (9,66). Quantitative analysis of the frequency and intensity of Cav1 staining in human GC tissue microarrays was performed by the expert pathologist C. Röcken as published previously (9).…”

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confidence: 99%

“…AGS clones stably transfected with Cav1 (AGS/Cav1) or empty vector (AGS/EV) were treated with 1 M rosiglitazone for 16 h. Total RNA (1 g) was labeled with a one-cycle cRNA labeling kit (Affymetrix, Wycombe, United Kingdom) and hybridized to HGU133 Plus 2.0 arrays (Affymetrix). Gene signatures were identified using gene set enrichment analysis (GSEA) (66). Reverse transcription-PCR (RT-PCR) and quantitative PCR (qPCR) were performed as published previously (9).…”

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confidence: 99%

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The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor γ through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain

Burgermeister

Friedrich

Hitkova

et al. 2011

Molecular and Cellular Biology

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a transcription factor that promotes differentiation and cell survival in the stomach. PPAR␥ upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPAR␥ is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPAR␥ signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPAR␥ and enhanced nuclear translocation and ligand-independent transcription of PPAR␥ target genes. In contrast, Cav1 overexpression sequestered PPAR␥ in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPAR␥'s ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the liganddependent transcriptional activity of PPAR␥ and to inhibit cell proliferation. Ligand-activated PPAR␥ also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPAR␥ regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPAR␥ to ligands, limiting proliferation of gastric epithelial cells.Peroxisome proliferator-activated receptor ␥ (PPAR␥) belongs to the nuclear receptor (NR) superfamily (31). Infection by Helicobacter pylori is a major risk factor for gastric cancer (GC) in humans (68). H. pylori increases the expression of PPAR␥, cytokines, and eicosanoids, while PPAR␥ protects the gastric epithelium by inhibiting apoptosis of host cells (19) and inflammation (42). PPAR␥ ligands (glitazones; 15-deoxy-prostaglandin J 2 ) have been shown to inhibit proliferation and induce growth arrest or apoptosis in human GC cell lines (32,52,53). PPAR␥ knockout (KO) mice are susceptible to chemically induced gastric carcinogenesis (36). In humans, the common "partial loss of function" gene polymorphism (Pro12Ala) is correlated with an increased risk of GC, suggesting a role for PPAR␥ as a tumor suppressor in the stomach (67).PPAR␥ inhibits cell proliferation by several mechanisms, including inhibition of cyclin D1 expression, promotion of its proteasomal degradation, and upregulation of cyclin-dependent kinase (CDK) inhibitors (20,55,65). Members of the Ras/mitogen-activated protein kinase (MAPK) cascade, such as extracellular signal-regulated kinases 1/2 (ERK1/2), counteract this effect by inducing cyclin D1 expression and reducing PPAR␥ activity by phosphorylation on serine 84 (serine 82 in mouse) in its N-terminal activation function (AF1) (7). Cav1, a scaffold protein of plasma membrane caveolae (46), attenuates ERK1/2 activation and cell growth by sequestration of upstream MAPK cascade components, including growth factor receptors, Ras, Raf, and MEK1. In contrast, Cav1...

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confidence: 99%

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confidence: 99%

The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor γ through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain

Burgermeister

Friedrich

Hitkova

et al. 2011

Molecular and Cellular Biology

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“…In one study, fatalities occurred in mice that had been fed with 1% bile acid and subjected to 70% hepatectomy, suggesting that bile acid not only failed to promote liver regeneration, but was likely to be cytotoxic, perhaps as a result of the higher dose to that employed in the present study (21). Furthermore, the mRNA expression of FXR in 2/3 hepatectomy rats was significantly increased, and the hepatic regeneration rate of FXR-knockout mice subjected to 70% hepatectomy, was shown to be inhibited (11). In addition, FXR alleviated age-related proliferation defects by activating Fork head Box m1b transcription in regenerating mouse livers (22), and was also shown to regulate liver repair following CCl 4 -induced toxic injury (23).…”

Section: Discussionmentioning

confidence: 69%

“…FXR is predominantly expressed in the liver, kidney, intestine and adrenal glands, and is involved in regulating the metabolism of bile acid and cholesterol (8,9). Furthermore, the interaction of bile acid with FXR is essential for glucose metabolism, liver inflammation and liver regeneration (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats

Ding

Yang

et al. 2015

Molecular Medicine Reports

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Abstract. Bile acids, which are synthesized from cholesterol in the hepatocytes of the liver, are amphipathic molecules with a steroid backbone. Studies have shown that bile acid exhibits important effects on liver regeneration. However, the mechanism underlying these effects remains unclear. The aim of the present study was to investigate the effect of bile acid and the farnesoid X receptor (FXR) on hepatic regeneration and lipid metabolism. Rats were fed with 0.2% bile acid or glucose for 7 days and then subjected to a 50 or 70% hepatectomy. Hepatic regeneration rate, serum and liver levels of bile acid, and expression of FXR and Caveolin-1, were detected at 24, 48 or 72 h following hepatectomy. The expression of proliferating cell nuclear antigen (PCNA) in the liver was measured using immunohistochemistry at the end of the study. Hepatocytes isolated from rats were treated with bile acid, glucose, FXR agonist and FXR antagonist, separately or in combination. Lipid metabolism, the expression of members of the FXR signaling pathway and energy metabolism-related factors were measured using ELISA kits or western blotting. Bile acid significantly increased the hepatic regeneration rate and the expression of FXR, Caveolin-1 and PCNA. Levels of total cholesterol and high density lipoprotein were increased in bile acid-or FXR agonist-treated hepatocytes in vitro. Levels of triglyceride, low density lipoprotein and free fatty acid were decreased. In addition, bile acid and FXR agonists increased the expression of bile salt export pump and small heterodimer partner, and downregulated the expression of apical sodium-dependent bile acid transporter, Na + /taurocholate cotransporting polypeptide and cholesterol 7α-hydroxylase. These results suggested that physiological concentrations of bile acid may promote liver regeneration via FXR signaling pathways, and may be associated with energy metabolism. IntroductionLiver regeneration is important in the recovery from injury induced by surgery, trauma, poisoning, infection, necrosis or liver transplantation (1). Consequently, research investigating the improvement of the regeneration ability of the liver, is of great significance. During regeneration, quiescent mature hepatocytes reenter the cell cycle in order to proliferate and divide, thus leading to hepatic regeneration without the involvement of stem cells. Although the exact mechanisms have not been fully characterized, a study demonstrated that liver regeneration primarily comprises cell proliferation, lipid metabolism, various growth factors, and a number of cytokines and their signaling pathways (2).Bile acid, which is synthesized from cholesterol, is the chief components of bile. The primary functions of bile are to digest the fat soluble molecules in food and to aid in the intestinal absorption of lipids in vivo. Recent studies have shown that bile acid acts as a signaling molecule by activating signaling pathways, and that it participates in the process of liver regeneration (3,4). A number of transport proteins fo...

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“…For the analysis of the FXR, RT-qPCR was used to detect FXR mRNA level. Primer sequence for FXR was designed according to previous reports [20,21].…”

Section: Rt-qpcr and Western Blot Analysismentioning

confidence: 99%

Activation of farnesoid X receptor attenuates liver injury in systemic lupus erythematosus

et al. 2011

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To investigate the expression and effect of farnesoid X receptor (FXR) on systemic lupus erythematosus (SLE) liver dysfunction and indicate its hepatoprotective role and the immunomodulatory property. mRNA and protein levels of FXR were determined on the liver specimens of SLE patients with liver injury as well as MRL/lpr rodent models. The FXR agonist chenodeoxycholic acid (CDCA) was administrated to MRL/lpr mice and the control BALB/C with concanavalin A (ConA)-induced liver injury. Blood samples were taken 0, 4, 8, 12, 16, and 24 h after ConA injection for the detection of serum ALT, AST, IFN-γ, TNF-α, and IL-6. FXR was down-regulated at both mRNA and protein levels in the liver specimens of SLE patients with liver injury as well as MRL/lpr mice. MRL/lpr was more susceptible to ConA than BALB/C indicated by significantly higher levels of aminotransferase and inflammatory cytokines. Activation of FXR by CDCA significantly reduced aminotransferase and inflammatory cytokines IFN-γ, TNF-α, and IL-6 caused by ConA injection in MRL/lpr mice. FXR was down-regulated in SLE patients as well as MRL/lpr lupus models with liver dysfunction. FXR activation ameliorated liver injury and suppressed inflammatory cytokines, thereby showing its protective function in SLE. Our findings raised the promising potential target for the treatment of SLE liver injury.

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Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid–induced liver hypertrophy†

Cited by 28 publications

References 54 publications

The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor γ through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain

The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor γ through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain

Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats

Activation of farnesoid X receptor attenuates liver injury in systemic lupus erythematosus

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