Dehydroepiandrosterone Sulfotransferase Gene Induction by Bile Acid Activated Farnesoid X Receptor

Song, Chenchen; Echchgadda, Ibtissam; Baek, Bong Sook; Ahn, Soon Cheol; Oh, Taesung; Roy, Arun K.; Chatterjee, Bandana

doi:10.1074/jbc.m107557200

Cited by 185 publications

(137 citation statements)

References 41 publications

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“…These include the transport proteins BSEP, NTCP, and IBABP, as well as proteins affecting bile acid synthesis like CYP7A1, CYP8B1, and SHP. In addition, dehydroepiandrosterone-sulfotransferase, an enzyme with bile acid sulfo-conjugating activity, is directly regulated by FXR suggesting involvement also in bile acid detoxification and clearance (11). 1-6) or GW4064 (lanes 7-12) for 7 days as described under "Experimental Procedures."…”

Section: Discussionmentioning

confidence: 99%

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Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

164

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Section: Discussionmentioning

confidence: 99%

“…In contrast to this IR-1 arrangement, FXR has also been shown to bind and activate an inverted repeat without a spacing nucleotide (IR-0). This IR-0 arrangement was found to be the cognate FXR element in the dehydroepiandrosterone sulfotransferase gene, which encodes an enzyme with bile acid sulfo-conjugating activity (11).…”

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confidence: 99%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

164

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“…Bile acids are natural ligands for the nuclear receptor, farnesoid X receptor (FXR), and the plasma membranebound bile acid receptor TGR5 [also known as G protein-coupled bile acid receptor 1 (Gpbar1); membrane-type receptor for bile acids (M-BAR)]. Through activation of these receptors bile acids regulate lipid (9-11), glucose (12-16), and energy homeostasis (17) in addition to regulating their own synthesis (18), conjugation (19), transport (20)(21)(22), and detoxification (19,23,24). The global signaling capacity of bile acids is currently unclear; however, the expression of bile acid receptors FXR and TGR5 in tissues outside of the enterohepatic circulation, including the kidney (25) and heart (26, 27), suggests a greater role throughout the body.…”

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confidence: 99%

Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Swann

Want

Geier

et al. 2010

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

626

473

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We elucidate the detailed effects of gut microbial depletion on the bile acid sub-metabolome of multiple body compartments (liver, kidney, heart, and blood plasma) in rats. We use a targeted ultraperformance liquid chromatography with time of flight mass-spectrometry assay to characterize the differential primary and secondary bile acid profiles in each tissue and show a major increase in the proportion of taurine-conjugated bile acids in germ-free (GF) and antibiotic (streptomycin/penicillin)-treated rats. Although conjugated bile acids dominate the hepatic profile (97.0 ± 1.5%) of conventional animals, unconjugated bile acids comprise the largest proportion of the total measured bile acid profile in kidney (60.0 ± 10.4%) and heart (53.0 ± 18.5%) tissues. In contrast, in the GF animal, taurine-conjugated bile acids (especially taurocholic acid and tauro-β-muricholic acid) dominated the bile acid profiles (liver: 96.0 ± 14.5%; kidney: 96 ± 1%; heart: 93 ± 1%; plasma: 93.0 ± 2.3%), with unconjugated and glycine-conjugated species representing a small proportion of the profile. Higher free taurine levels were found in GF livers compared with the conventional liver (5.1-fold; P < 0.001). Bile acid diversity was also lower in GF and antibiotic-treated tissues compared with conventional animals. Because bile acids perform important signaling functions, it is clear that these chemical communication networks are strongly influenced by microbial activities or modulation, as evidenced by farnesoid X receptor-regulated pathway transcripts. The presence of specific microbial bile acid co-metabolite patterns in peripheral tissues (including heart and kidney) implies a broader signaling role for these compounds and emphasizes the extent of symbiotic microbial influences in mammalian homeostasis.farnesoid X receptor | gut microbiota | TGR5 | ultra-performance liquid chromatography mass spectrometry | G protein-coupled bile acid receptor 1 T he importance of gut microbiome variation in relation to human health and diverse diseases is now well-recognized (1-4). The microbiome is a virtual organ that performs many digestive and metabolic functions for the host, including enhanced calorific recovery from ingested foods and degradation of complex plant polysaccharides. Microbial communities have coevolved with man and show remarkable diversity dependent on topographical location and interperson variability (5). Co-evolution has refined the microbiome of organisms to a state where metabolic complementarity exists within the microbiota (6), and important biosynthetic/ metabolic pathways are provided for the host that significantly extend host metabolic capacity (3). As such, the mammalian host can be considered a superorganism (7), whose metabolism is the sum of that of both the host and the collective microbial community. The enterohepatic circulation provides a vehicle for this transgenomic metabolism, and bile acids, whose functional role in the global mammalian system is multifaceted, are an important class of metabolites that u...

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“…With two exceptions, FXREs consist of an inverted repeat of the canonical hexanucleotide core motif PuGGTCA spaced by one base pair (IR1) (16). Recently, an inverted repeat with no spacer (IR0) in the dehydroepiandrosterone sulfotransferase gene (22) and an everted repeat of the core motif separated by 8 nucleotides (ER8) in the multidrug resistance-associated protein 2 (MRP2) gene (23) have also been reported as elements required for FXR-dependent transcriptional activation. FXR acts as a bile acid sensor in the liver, where it mediates the negative feedback of bile acid biosynthesis via induction of small heterodimer partner (NR0B2) and subsequent repression of cholesterol 7␣-hydroxylase gene (CYP7A1) expression (24 -27), the rate-limiting enzyme in this pathway, and the sterol 12␣-hydroxylase gene (CYP8B1), the specific enzyme required for cholic acid synthesis (28).…”

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confidence: 99%

The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-α and Contains a Novel Farnesoid X-activated Receptor Response Element

Prieur

Coste

Rodríguez

2003

Journal of Biological Chemistry

172

137

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The newly identified apolipoprotein AV (apoAV) gene is a key player in determining plasma triglyceride concentrations. Because hypertriglyceridemia is a major independent risk factor in coronary artery disease, the understanding of the regulation of the expression of this gene is of considerable importance. We presently characterize the structure, the transcription start site, and the promoter of the human apoAV gene. Since the peroxisome proliferator-activated receptor-␣ (PPAR␣) and the farnesoid X-activated receptor (FXR) have been shown to modulate the expression of genes involved in triglyceride metabolism, we evaluated the potential role of these nuclear receptors in the regulation of apoAV transcription. Bile acids and FXR induced the apoAV gene promoter activity. 5-Deletion, mutagenesis, and gel shift analysis identified a heretofore unknown element at positions ؊103/؊84 consisting of an inverted repeat of two consensus receptor-binding hexads separated by 8 nucleotides (IR8), which was required for the response to bile acid-activated FXR. The isolated IR8 element conferred FXR responsiveness on a heterologous promoter. On the other hand, in apoAV-expressing human hepatic Hep3B cells, transfection of PPAR␣ specifically enhanced apoAV promoter activity. By deletion, site-directed mutagenesis, and binding analysis, a PPAR␣ response element located 271 bp upstream of the transcription start site was identified. Finally, treatment with a specific PPAR␣ activator led to a significant induction of apoAV mRNA expression in hepatocytes. The identification of apoAV as a PPAR␣ target gene has major implications with respect to mechanisms whereby pharmacological PPAR␣ agonists may exert their beneficial hypotriglyceridemic actions.Recent epidemiological studies have shown that hypertriglyceridemia is a major independent risk factor for coronary heart disease, which remains as a major cause of mortality in the Western world (1-6). Understanding the factors that control plasma triglyceride levels and the genes that primarily reflect circulating concentrations of triglyceride-rich lipoproteins is thus of major importance and may provide new opportunities for therapeutic intervention in atherogenic dyslipidemia.Pharmacological activation of peroxisome proliferator-activated receptor-␣ (PPAR␣ 1 ; NR1C1) lowers plasma levels of triglyceride-rich lipoproteins markedly (7,8). PPAR␣ is a fatty acid-activated nuclear transcription factor that regulates the expression of genes involved in lipid and energy metabolism (9, 10). PPAR␣ heterodimerizes with the retinoid X receptor ␣ (RXR␣; NR2B1) and binds to specific DNA sequence elements, designated PPREs, which consist of a direct repeat of the hexanucleotide core motif PuGGTCA separated by 1 or 2 nucleotides (DR1 or DR2). PPAR␣ mediates the hypotriglyceridemic effect of fibrates by regulating the transcription of key genes associated with different intra-and extracellular metabolic pathways. Fibrates increase cellular fatty acid transport and uptake, conversion to acyl-CoA deriv...

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Dehydroepiandrosterone Sulfotransferase Gene Induction by Bile Acid Activated Farnesoid X Receptor

Cited by 185 publications

References 41 publications

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-α and Contains a Novel Farnesoid X-activated Receptor Response Element

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