The Farnesoid X-activated Receptor Mediates Bile Acid Activation of Phospholipid Transfer Protein Gene Expression

Urizar, Nancy L.; Dowhan, Dennis H.; Moore, David D.

doi:10.1074/jbc.m007998200

Cited by 219 publications

(149 citation statements)

References 28 publications

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“…FXR also activates transcription of the ileal bile acid-binding protein (IBABP) and phospholipid transfer protein (PLTP) genes via IR-1 elements in the promoters of these genes (9,10). 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).…”

mentioning

confidence: 99%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

169

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mentioning

confidence: 99%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

169

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“…FXR prefers binding to an inverted repeat of hormone response element (HRE), AG(G/T)TCA, with one nucleotide spacing (inverted repeat 1) (18,19). FXR-activated genes so far identified are intestinal bile acid-binding protein (20), serum phospholipid transfer protein (21), and canalicular bile salt expert pump (22) genes. However, FXR inhibits CYP7A1 transcription by an indirect mechanism involving other liver-specific transcription factors (23).…”

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confidence: 99%

Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)

Zhang

Chiang

2001

Journal of Biological Chemistry

217

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Sterol 12␣-hydroxylase catalyzes the synthesis of cholic acid and controls the ratio of cholic acid over chenodeoxycholic acid in the bile. Transcription of CYP8B1 is inhibited by bile acids, cholesterol, and insulin. To study the mechanism of CYP8B1 transcription by bile acids, we have cloned and determined 3389 base pairs of the 5-upstream nucleotide sequences of the human CYP8B1. Deletion analysis of CYP8B1/luciferase reporter activity in HepG2 cells revealed that the sequences from ؊57 to ؉300 were important for basal and liver-specific promoter activities. Hepatocyte nuclear factor 4␣ (HNF4␣) strongly activated human CYP8B1 promoter activities, whereas cholesterol 7␣-hydroxylase promoter factor (CPF), an NR5A2 family of nuclear receptors, had much less effect. Electrophoretic mobility shift assay identified an overlapping HNF4␣-and CPFbinding site in the ؉198/؉227 region. The human CYP8B1 promoter activities were strongly repressed by bile acids, and the bile acid response element was localized between ؉137 and ؉220. Site-directed mutagenesis of the HNF4␣-binding site markedly reduced promoter activity and its response to bile acid repression. On the other hand, mutation of the CPF-binding site had little effect on promoter activity and bile acid inhibition. A negative nuclear receptor, small heterodimer partner markedly inhibited transactivation of CYP8B1 by HNF4␣. Mammalian two-hybrid assay confirmed that HNF4␣ interacted with small heterodimer partner. Furthermore, bile acids and farnesoid X receptor reduced the expression of nuclear HNF4␣ in HepG2 cells and rat livers and its binding to DNA. Bile acids and farnesoid X receptor also inhibited mouse HNF4␣ gene transcription. In summary, our data revealed the critical roles HNF4␣ play on CYP8B1 transcription and its repression by bile acids. Bile acids repress human CYP8B1 transcription by reducing the transactivation activity of HNF4␣ through interaction of HNF4␣ with SHP and reduction of HNF4␣ expression in the liver.

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“…Other FXR target genes encode the secreted proteins phospholipid transfer protein (PLTP) (17,18), apoE (19), and apoCII (20), all known to be involved in the metabolism of plasma lipids and lipoproteins. The observation that plasma triglyceride levels declined when rodents were treated with either a synthetic (GW4064) (21) or a natural (CDCA) FXR ligand (20) is consistent with the hypothesis that activation of FXR modulates lipoprotein levels.…”

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confidence: 99%

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

Anisfeld

Kast-Woelbern

Meyer

et al. 2003

Journal of Biological Chemistry

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Syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that participates in the binding and internalization of extracellular ligands, was identified in a screen designed to isolate genes that are regulated by the farnesoid X-receptor (FXR, NR1H4). Treatment of human hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands resulted in both induction of SDC1 mRNA and enhanced binding, internalization, and degradation of low density lipoprotein. Transient transfection assays, using wild-type and mutant SDC1 promoter-luciferase genes, led to the identification of a nuclear hormone receptor-binding hexad arranged as a direct repeat separated by one nucleotide (DR-1) in the proximal promoter that was necessary and sufficient for activation by FXR. The wild-type, but not a mutated DR-1 element, conferred FXR responsiveness to a heterologous thymidine kinase promoter-reporter gene. Four murine FXR isoforms have been identified recently that differ either at their amino terminus and/or by the presence or absence of four amino acids in the hinge region. Interestingly, the activities of the human SDC1 promoter-reporter constructs were highly induced by the two FXR isoforms that do not contain the four-amino acid insert and were unresponsive to the isoforms containing the four amino acids. Thus, current studies demonstrate that hepatic SDC1 is induced in an FXR isoform-specific manner. Increased expression of SDC1 may account in part for the hypotriglyceridemic effect that can result from the administration of chenodeoxycholic acid to humans.

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The Farnesoid X-activated Receptor Mediates Bile Acid Activation of Phospholipid Transfer Protein Gene Expression

Cited by 219 publications

References 28 publications

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)

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

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