Identification of a bile acid response element in the cholesterol 7 alpha-hydroxylase gene CYP7A

Stroup, Diane; Crestani, Maurizio; Chiang, John Y.L.

doi:10.1152/ajpgi.1997.273.2.g508

Cited by 61 publications

(80 citation statements)

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“…63 Because the amount of deoxycholate infused represented only 24% of the cholate dose, a superior suppressive capacity of this more hydrophobic bile acid is likely, at least under physiological conditions. Recent studies in human HepG2 cells support 15,16,64 the role of hydrophobicity for regulation of bile acid synthesis. Our studies in healthy volunteers 19 clearly support such an assumption, although a reduced capability of conjugated cholate uptake in HepG2 cells 15 may have contributed to these observations in this experimental system.…”

Section: Discussionmentioning

confidence: 93%

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

et al. 1999

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Hepatic bile acid synthesis is regulated by recirculating bile acids, possibly by modulating the availability of newly synthesized and preformed cholesterol. Because data in the hamster on this mechanism are lacking, we fitted these animals with an extracorporeal bile duct and administered tritiated water intraperitoneally to label newly formed cholesterol. After interruption of the enterohepatic circulation, physiological and double-physiological doses of conjugated cholate (25 or 50 mol/100 g · h) or of unconjugated deoxycholate (6 or 12 mol) were infused intraduodenally for 54 hours and compared with controls. De novo and preformed cholesterol directly secreted into bile or used for cholate and chenodeoxycholate synthesis were quantitated by high-pressure liquid chromatography (HPLC)-liquid scintillation. Directly after depletion of the bile acid pool (6-9 hours) at nearly physiological conditions, chenodeoxycholate synthesis was significantly reduced by cholate and deoxycholate by up to 45% to 51%, whereas cholate formation decreased by Ϸ22% during deoxycholate. This short-term effect was mainly mediated by reduced synthesis from preformed cholesterol. After long-term bile depletion (30-54 hours), bile acid synthesis returned to control levels during 25 mol of cholate and of both deoxycholate doses. In contrast, only 50 mol of cholate prevented derepression of bile acid synthesis. This long-term effect was mainly attributed to a diminished formation from de novo cholesterol exceeding the reduced synthesis from preformed cholesterol. In summary, short-and long-term regulation of bile acid synthesis in hamsters differs with respect to availabilities of preformed and de novo cholesterol. (HEPATOL-OGY 1999;30:230-237.)

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Section: Discussionmentioning

confidence: 93%

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

et al. 1999

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“…It has been reported that the ranking order of bile acid inhibition of bile acid synthetic enzymes is CYP8B1 Ͼ CYP7A1 Ͼ CYP27A1 (11). We have identified previously the bile acid response elements (BAREs) in the CYP7A1, and we proposed a nuclear hormone receptor-mediated mechanism for bile acid feedback inhibition of CYP7A1 transcription (4,13,14). This hypothesis has now been supported by the identification of a nuclear receptor, farnesoid x receptor (FXR), as a bile acid-activated receptor (15)(16)(17).…”

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confidence: 97%

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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“…Ligandbound FXR regulates a number of target genes involving BA transport and metabolism (6). BAs also feedback-regulate BA biosynthesis, where activated FXR induces small heterodimer partner (SHP/NR0B2) gene expression, and SHP in turn inhibits liver receptor homolog 1 (LRH-1/NR5A2) or hepatocyte nuclear factor 4␣ (HNF4␣/NR2A1) activities on the BA response elements (BAREs) of CYP7A1 and CYP8B1 promoters (7)(8)(9)(10). BAs can also act via FXR-independent pathways that use PKC (11) and JNK signaling (12,13) to suppress HNF4␣-mediated expression of human CYP8B1 (hCYP8B1) (10,11,14).…”

mentioning

confidence: 99%

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Sanyal

Båvner

Haroniti

et al. 2007

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

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Coordinated regulation of bile acid biosynthesis, the predominant pathway for hepatic cholesterol catabolism, is mediated by few key nuclear receptors including the orphan receptors liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), small heterodimer partner (SHP), and the bile acid receptor FXR (farnesoid X receptor). Activation of FXR initiates a feedback regulatory loop via induction of SHP, which suppresses LRH-1-and HNF4␣-dependent expression of cholesterol 7␣ hydroxylase (CYP7A1) and sterol 12␣ hydroxylase (CYP8B1), the two major pathway enzymes. Here we dissect the transcriptional network governing bile acid biosynthesis in human liver by identifying GPS2, a stoichiometric subunit of a conserved corepressor complex, as a differential coregulator of CYP7A1 and CYP8B1 expression. Direct interactions of GPS2 with SHP, LRH-1, HNF4␣, and FXR indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes. In addition, species-specific differences in the regulation of bile acid biosynthesis were uncovered by identifying human CYP8B1 as a direct FXR target gene, which has implications for therapeutic approaches in bile acid-related human disorders.cholesterol 7␣ hydroxylase ͉ sterol 12␣ hydroxylase ͉ farnesoid X receptor ͉ small heterodimer partner B ile acids (BAs) are cholesterol derivatives essential for absorption of dietary lipids and fat-soluble vitamins and maintenance of cholesterol BA homeostasis (1, 2). In humans the major BA biosynthetic pathway is initiated by cholesterol 7␣ hydroxylase (CYP7A1) to produce two primary BAs, cholic acid and chenodeoxycholic acid (CDCA). Sterol 12␣ hydroxylase (CYP8B1) catalyzes the synthesis of cholic acid and determines the ratio of cholic acid to CDCA in the bile (1). In addition to emulsification of dietary lipids, cholic acid and CDCA are ligands for farnesoid X receptor (FXR/NR1H4) (3-5). Ligandbound FXR regulates a number of target genes involving BA transport and metabolism (6). BAs also feedback-regulate BA biosynthesis, where activated FXR induces small heterodimer partner (SHP/NR0B2) gene expression, and SHP in turn inhibits liver receptor homolog 1 (LRH-1/NR5A2) or hepatocyte nuclear factor 4␣ (HNF4␣/NR2A1) activities on the BA response elements (BAREs) of CYP7A1 and CYP8B1 promoters (7-10). BAs can also act via FXR-independent pathways that use PKC (11) and JNK signaling (12, 13) to suppress HNF4␣-mediated expression of human CYP8B1 (hCYP8B1) (10,11,14). Although the physiological role of SHP in BA biosynthesis is well documented, mechanistic details of repression by SHP remain unclear. Recent studies indicate that SHP may repress its targets (i) via direct binding and blocking the coactivator interaction interface of its target nuclear receptors (NRs), (ii) by antagonizing CREB binding protein (CBP)/p300-dependent coactivator functions on NRs via recruitment of a coinhibitor protein like EID1, and (iii) by recruiting corepressor complexes that include histone deacetylases (HDAC) 1, 3, and 6, Sin3A...

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Identification of a bile acid response element in the cholesterol 7 alpha-hydroxylase gene CYP7A

Cited by 61 publications

References 0 publications

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

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

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

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