The Negative Effects of Bile Acids and Tumor Necrosis Factor-α on the Transcription of Cholesterol 7α-Hydroxylase Gene (CYP7A1) Converge to Hepatic Nuclear Factor-4

Fabiani, Emma De; Mitro, Nico; Anzulovich, Ana Cecilia; Pinelli, A; Galli, Giovanni; Crestani, Maurizio

doi:10.1074/jbc.m103270200

Cited by 177 publications

(153 citation statements)

References 38 publications

(40 reference statements)

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“…A. M., unpublished observations). HNF4 is an important regulator of CYP7A1 expression in different species and is at least in part responsible for mediating CYP7A1 repression by bile acids [76,78,79].…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

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Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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“…Mammalian Two-hybrid Assay-Gal4/HNF4␣ fusion construct (provided by M. Crestani (33)) was prepared by inserting the full-length HNF4␣ coding region (amino acid residue 1-455) into plasmid pcDNA3X(Ϫ) (Invitrogen) at the BamHI site. VP16-SHP (provided by D. Mangelsdorf (24)) contained a full-length mouse SHP coding region ligated into pCMX-VP16.…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Chiang

2001

Journal of Biological Chemistry

211

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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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“…4,24,25 An alternative mechanism for the feedback inhibition of CYP7A transcription is through the effects of bile acids and inflammatory cytokines tumor necrosis factor ␣ and interleukin 1␤ in recruiting the mitogen-activated protein kinase cascade (JNK pathways), 26 -29 resulting in the activation of the short heterodimer protein repressor protein 26 or the inhibition of HNF-4␣ binding to the DR1 sequence of the CYP7A1 promoter BARE II region. 28 HNF-6 hepatocyte transcription factor belongs to the network of hepatocyte-enriched nuclear factors that have potential binding sites for numerous target genes essential to liver differentiation and function. In vivo, HNF-6 also participates in the hepatic injury repair response to bile duct ligation by regulating the bile duct cell proliferative reponse to biliary obstruction.…”

Section: Hnf-6 Foxa1mentioning

confidence: 99%

In vivo regulation of murine CYP7A1 by HNF-6: A novel mechanism for diminished CYP7A1 expression in biliary obstruction

et al. 2004

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Disruption of the enterohepatic bile acid circulation during biliary tract obstruction leads to profound perturbation of the cholesterol and bile acid metabolic pathways. Several families of nuclear receptor proteins have been shown to modulate this critical process by regulating hepatic cholesterol catabolism and bile acid synthesis through the transcriptional control of cholesterol 7-␣ hydroxylase (CYP7A1). Hepatocyte nuclear factor (HNF) 6 (also known as OC-1) is a member of the ONECUT family of transcription factors that activate numerous hepatic target genes essential to liver function. We have previously shown that hepatic expression of mouse HNF-6 messenger RNA (mRNA) and protein significantly decrease following bile duct ligation. Because CYP7A1 contains potential HNF-6 binding sites in its promoter region, we tested the hypothesis that HNF-6 transcriptionally regulates CYP7A1. Following bile duct ligation, we demonstrated that diminished HNF-6 mRNA levels correlate with a reduction in CYP7A1 mRNA expression. Increasing hepatic levels of HNF-6 either by infection with recombinant adenovirus vector expressing HNF-6 cDNA by growth hormone treatment leads to an induction of CYP7A1 mRNA. To directly evaluate if HNF-6 is a transcriptional activator for CYP7A1, we used deletional and mutational analyses of CYP7A1 promoter sequences and defined sequences ؊206/؊194 to be critical for CYP7A1 transcriptional stimulation by HNF-6 in cotransfection assays. In conclusion, the HNF-6 protein is a component of the complex network of hepatic transcription factors that regulates the expression of hepatic genes essential for bile acid homeostasis and cholesterol/lipid metabolism in normal and pathological conditions.

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The Negative Effects of Bile Acids and Tumor Necrosis Factor-α on the Transcription of Cholesterol 7α-Hydroxylase Gene (CYP7A1) Converge to Hepatic Nuclear Factor-4

Cited by 177 publications

References 38 publications

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

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

In vivo regulation of murine CYP7A1 by HNF-6: A novel mechanism for diminished CYP7A1 expression in biliary obstruction

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