Syndecan-1 Expression Is Regulated in an Isoform-specific Manner by the Farnesoid-X Receptor

Anisfeld, Andrew M.; Kast-Woelbern, Heidi R.; Meyer, Marie E.; Jones, Stacey A.; Zhang, Yanqiao; Williams, Kevin Jon; Willson, Timothy M.; Edwards, Peter A.

doi:10.1074/jbc.m302505200

Cited by 80 publications

(72 citation statements)

References 37 publications

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“…Thymidine kinase (TK)-Luc reporter constructs under the control of two copies of either LXRE-3 or LXRE-6 were generated by annealing double-stranded oligonucleotides and then ligating the DNA into BamH1-digested pTK-Luc (30). Transient transfection of HepG2 cells was performed in triplicate in 48-well plates as described (29,31). Briefly, reporter constructs (100 ng) and pCMV-␤-galactosidase (50 ng) were transiently transfected with either pCMX-LXR␣ (50 ng), pCMX-RXR␣ (5 ng) expression vectors, and/or control plasmid (pTKCIII) (total of 205 ng/well).…”

Section: Methodsmentioning

confidence: 99%

Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein

Nakamura¹,

Kennedy²,

Baldán³

et al. 2004

Journal of Biological Chemistry

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156

128

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The murine Abcg1 gene is reported to consist of 15 exons that encode a single mRNA (herein referred to as Abcg1-a) and protein. We now demonstrate that (i) the murine gene contains two additional coding exons downstream of exon 1, (ii) transcription involves the use of multiple promoters, and (iii) the RNA undergoes alternative splicing reactions. As a result, three mRNAs are expressed that encode three putative protein isoforms that differ at their amino terminus. ABCG1 transcripts are induced in vivo in multiple tissues in response to the liver X receptor ligand T0901317. Identification and characterization of four liver X receptor response elements in the intron downstream of exon 2 provides a mechanism by which this induction occurs. Importantly, cholesterol efflux to high density lipoprotein was stimulated following transfection of Hek293 cells with plasmids encoding individual ABCG1 isoforms. In situ hybridization studies in embryonic day 11.5-15.5 mouse embryos revealed strong expression of ABCG1 transcripts in the olfactory epithelium, hind brain, eye, and dorsal root ganglia. The relatively high levels of expression in neuronal tissues and the eye suggest that ABCG1-dependent cholesterol efflux may be critical for normal neuronal function in addition to its role in macrophages.There are more than 373 members in the ATP-binding cassette (ABC)

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Section: Methodsmentioning

confidence: 99%

Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein

Nakamura¹,

Kennedy²,

Baldán³

et al. 2004

Journal of Biological Chemistry

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156

128

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“…This approach identified several genes, including those encoding FBG ␣ , -␤ , and -␥ , whose mRNAs appeared to be induced by treatment of the cells with either natural or synthetic FXR ligands. Other genes identified by this approach, including apolipoprotein C-II (apoC-II), syndecan-1 (SDC1), and MRP2, have been reported elsewhere and are involved in either bile acid or lipoprotein transport and metabolism (17,24,42). We chose to explore the regulation of the FBG genes by FXR because their function in clotting represents an entirely new signaling paradigm that potentially links coagulation and clotting to bile acids.…”

Section: Induction Of Fbg ␣ -␤ and -␥ By Natural And Synthetic Fxmentioning

confidence: 99%

“…One group, which includes the ABC transporters BSEP (21,23), multidrug resistanceassociated protein 2 (MRP2) (24), multidrug resistance protein, MDR3 (human) (25), and rodent Mdr2 (26), together with the fibroblast growth factor-19 (27) and the small heterodimeric partner (SHP) (28)(29)(30)(31), functions to decrease hepatic bile acid concentrations by increasing export and decreasing bile acid synthesis. A second group of FXR target genes encode proteins that influence lipoprotein levels in the serum and decrease plasma triglycerides (17,22,28,(32)(33)(34)(35). The identification of this latter group of FXR target genes may help explain the molecular mechanism underlying the observations that administration of chenodeoxycholate to humans resulted in decreased plasma triglyceride levels (36).…”

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confidence: 99%

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Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling

Anisfeld

Kast-Woelbern

Lee

et al. 2005

Journal of Lipid Research

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Three genes, fibrinogen-␣ (FBG ␣ ), -␤ , and -␥ , encode proteins that make up the mature FBG protein complex. This complex is secreted from the liver and plays a key role in coagulation in response to vascular disruption. We identified all three FBG genes in a screen designed to isolate genes that are regulated by the farnesoid X receptor (FXR; Supplementary key words farnesoid X receptor • chenodeoxycholic acid • 3-(2,6-dichlorophenyl)-4-(3 Ј -carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole • nuclear hormone receptor Secretion of fibrinogen (FBG) from hepatocytes into the blood is a key component of the coagulation pathway that ultimately leads to the formation of a fibrous clot in response to vascular disruption (1). The mature FBG protein is a hexamer that is formed from disulfide-linked equimolar ratios of three peptides encoded by the FBG ␣ , -␤ , and -␥ genes (2). FBG expression is restricted almost entirely to the hepatocyte (3). In response to disruption of the vasculature, a signaling cascade originating from either the intrinsic or the extrinsic coagulation pathway leads to the activation of thrombin, which then cleaves small peptides, termed A and B, from the FBG hexamer, allowing fibrin to form (3). Fibrin can self-associate to form filaments that aggregate to form a meshwork of interconnected thick fibers that are a critical component of the clot (3). The activation of thrombin, and thus the production of fibrin, is regulated by a series of enzymes that respond to disruption of the vasculature to initiate the blood coagulation process (3). The production of fibrin is also regulated at the transcriptional level by expression of the FBG ␣ , -␤ , and -␥ genes in the hepatocyte (4).NR1H4The three FBG genes are clustered in a 65 kb region on human chromosome 4 (5, 6). Hepatic-specific expression is achieved by the requirement for the liver-enriched transcription factor HNF-1 (7, 8). Expression of the three FBG genes is tightly regulated in a coordinated manner so that the expression of all three genes is induced in response to the same signal (9). Induction of rat and human FBG mRNAs occurs as part of the acute phase response that is activated by interleukin-6 (IL-6) and glucocorticoid signaling pathways (9-11). The coordinated regulation of all three FBG genes in response to IL-6 and glucocorticoids is achieved by the presence of distinct transcription factor binding sites flanking each of the three FBG genes rather than through a single common regulatory element (4, 10, 11).Abbreviations:apoC-II, apolipoprotein C-II; CDCA, chenodeoxycholic acid; DR-1, direct repeat with a 1 bp spacer; ER-8, everted repeat with an 8 bp spacer; FBG, fibrinogen; FXR, farnesoid X receptor; FXRE, farnesoid X receptor response element; GW4064, 3-(2,6-dichlorophenyl)-4-(3 Ј -carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole; hFXR, human farnesoid X receptor; hRXR ␣ , human retinoid X receptor ␣ ; I-BABP, ileal bile acid binding protein; IL-6, interleukin-6; IR-1, inverted repeat with a 1 ...

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“…The optimal DNA binding sequence for the FXR␣/RXR␣ heterodimer is an inverted repeat, composed of minor variants of two AGGTCA half-sites spaced by one nucleotide (IR-1) (9 -11). However, FXR␣/RXR␣ can bind to other sites, including everted and direct repeats (ER-8 and DR-1) to activate transcription (12,13).…”

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confidence: 99%

Regulation of the Sodium/Sulfate Co-transporter by Farnesoid X Receptor α

Lee

Hubbert

Osborne

et al. 2007

Journal of Biological Chemistry

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Fxr␣ is known to regulate a variety of metabolic processes, including bile acid, cholesterol, and carbohydrate metabolism. In this study, we show direct evidence that Fxr␣ is a key player in maintaining sulfate homeostasis. We identified and characterized the sodium/sulfate co-transporter (NaS-1; Slc13a1) as an Fxr␣ target gene expressed in the kidney and intestine. Electromobility shift assays, chromatin immunoprecipitation, and promoter reporter studies identified a single functional Fxr␣ response element in the second intron of the mouse Slc13a1 gene. Treatment of wild-type mice with GW4064, a synthetic Fxr␣ agonist, induced Slc13a1 mRNA in the intestine and kidney. Slc13a1 mRNA was also induced in the kidney and intestine of wild-type, but not Fxr␣ ؊/؊ mice, after treatment with the hepatotoxin ␣-naphthylisothiocyanate, which is known to result in elevated blood bile acid levels. Finally, we observed a decrease in Slc13a1 mRNA in the kidney and intestine of Fxr␣ ؊/؊ mice and a corresponding increase in urinary excretion of free sulfates as compared with wild-type mice. These results demonstrate that mouse Slc13a1 is a novel Fxr␣ target gene expressed in the kidney and intestine and that in the absence of Fxr␣, mice waste sulfate into the urine. Thus, Fxr␣ is necessary for normal sulfate homeostasis in vivo.

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Syndecan-1 Expression Is Regulated in an Isoform-specific Manner by the Farnesoid-X Receptor

Cited by 80 publications

References 37 publications

Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein

Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein

Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling

Regulation of the Sodium/Sulfate Co-transporter by Farnesoid X Receptor α

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