The nuclear bile acid receptor <scp>FXR</scp> controls the liver derived tumor suppressor histidine‐rich glycoprotein

Deuschle, Ulrich; Birkel, M.; Hambruch, Eva; Hornberger, Martin; Kinzel, Olaf; Perović-Ottstadt, Sanja; Schulz, Andreas; Hahn, Ulrike; Burnet, Michael; Kremoser, Claus

doi:10.1002/ijc.29312

Cited by 16 publications

(17 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A likely explanation is that hepatic BA uptake by transporters like sodium/taurocholate cotransporting polypeptide NTCP is rapidly reduced by hepatic FXR activation. 5,6 In contrast, when 0.5 mg/kg Px-102 was given to humans for 7 days, serum levels of BAs decreased, 12 and similar findings were reported following 7 days of treatment with modified FGF19, 11 underscoring the different response patterns following acute and chronic treatment.…”

Section: Impactsupporting

confidence: 59%

An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers

2018

View full text Add to dashboard Cite

Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7α-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7α-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.

show abstract

Section: Impactsupporting

confidence: 59%

An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers

2018

View full text Add to dashboard Cite

show abstract

“…Administration of A. ilicifolius extract reverted the activity of LDH to near normal in drug-treated animals may be due to the inhibition of glycolysis and render the protection to the membrane. Carbohydrate moieties of glycoprotein have been implicated in the transport of metabolites across cell membranes and also a direct relation between glycoproteins and tumor genesis is observed (Deuschle et al, 2015). In the present study, the levels of glycoproteins hexose, hexosamine and sialic acids were significantly increased in DEN induced cancer bearing animals.…”

Section: Discussionsupporting

confidence: 55%

Chemopreventive Effect of Acanthus ilicifolius Extract on Modulating Antioxidants, Lipid Peroxidation and Membrane Bound Enzymes in Diethyl Nitrosamine Induced Liver Carcinogenesis

Rajamanick¹,

Selvaraj²,

Satyavani³

et al. 2015

International J. of Cancer Research

View full text Add to dashboard Cite

Acanthus ilicifolius (Acanthaceae) has received considerable attention due to its wide range of traditional usage in Indian system of medicine. The chemopreventive effect of ethanol extracts of Acanthus ilicifolius (AIEE) on N-nitrosodiethylamine (DEN, 200 mg kgG 1 )-induced experimental liver tumour was investigated in male Wistar rats. Experimental rats were orally treated with AIEE (400 mg kgG 1 b.wt.) for 1 week before the injection of diethyl nitrosamine and continued to be 14 weeks. The changes of lipid peroxidation, antioxidants and membrane bound enzymes were studied in AIEE treated experimental and control rats. The result indicates AIEE treatment effectively suppressed liver tumour induced with DEN as revealed by decrease in the levels of extend of alanine transaminase, aspartate transaminase, alkaline phosphatase, lipid peroxidase, glutathione peroxidase and glutathione-S-transferase with a concomitant increase in enzymatic antioxidant (superoxide dismutase and catalase) levels when compared to those in liver tumour bearing rats. The result of the study concludes significant chemopreventive effect of AIEE against DEN induced liver tumour.

show abstract

“…Indeed, we observed a strong correlation between DNA methylation and HRG mRNA expression using the cBio cancer genomics portal ( Figure S6 B) 34 . Previous studies had found that HRG was a transcriptional target gene of nuclear bile acid receptor Farnesoid X receptor (FXR) in liver cells 35 . NF-κB binds to FXR and subsequently suppresses its transcriptional activity, leading to the downregulation of FXR downstream genes 36 , 37 .…”

Section: Resultsmentioning

confidence: 99%

HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma

et al. 2020

View full text Add to dashboard Cite

Background: Tumor necrosis factor receptor 1 (TNFR1) signaling plays a pleiotropic role in the development of hepatocellular carcinoma (HCC). The formation of TNFR1-complex I supports cell survival while TNFR1-complex II leads to apoptosis, and the underlying mechanisms of the transformation of these TNFR1 complexes in HCC remain poorly defined. Methods: The interaction protein of TNFR1 was identified by GST pulldown assay, immunoprecipitation and mass spectrometry. In vitro and in vivo assay were performed to explore the biological features and mechanisms underlying the regulation of TNFR1 signals by histidine-rich glycoprotein (HRG). Data from the public databases and HCC samples were utilized to analyze the expression and clinical relevance of HRG. Results: HRG directly interacted with TNFR1 and stabilized TNFR1 protein by decreasing the Lys(K)-48 ubiquitination mediated-degradation. The formation of TNFR1-complex II was prompted by HRG overexpression via upregulating Lys(K)-63 ubiquitination of TNFR1. Besides, overexpression of HRG suppressed expression of pro-survival genes by impairing the activation of NF-κB signaling in the presence of TNFR1. Moreover, downregulation of HRG was a result of feedback inhibition of NF-κB activation in HCC. In line with the pro-apoptotic switch of TNFR1 signaling after HRG induction, overexpression of HRG inhibited cell proliferation and increased apoptosis in HCC. Conclusions: Our findings illustrate a crucial role for HRG in suppressing HCC via inclining TNFR1 to a pro-apoptotic cellular phenotype. Restoring HRG expression in HCC tissues might be a promising pharmacological approach to blocking tumor progression by shifting cellular fate from cell survival to apoptosis.

show abstract

The nuclear bile acid receptor FXR controls the liver derived tumor suppressor histidine‐rich glycoprotein

Cited by 16 publications

References 41 publications

An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers

An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers

Chemopreventive Effect of Acanthus ilicifolius Extract on Modulating Antioxidants, Lipid Peroxidation and Membrane Bound Enzymes in Diethyl Nitrosamine Induced Liver Carcinogenesis

HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma

Contact Info

Product

Resources

About