Feedback regulation of bile acid synthesis in human liver: Importance of HNF-4α for regulation of CYP7A1

Abrahamsson, Anna; Gustafsson, Ulf; Ellis, Ewa; Nilsson, Lisa-Mari; Sahlin, Staffan; Björkhem, Ingemar; Einarsson, Curt

doi:10.1016/j.bbrc.2005.02.170

Cited by 47 publications

(40 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are consistent with earlier reports, showing strong repression of CYP7A1 but little or no repression of CYP8B1 by CDCA in human (28,29), and demonstrate that these regulatory differences can be recapitulated in HepG2 cells.…”

Section: Differential Regulation Of Cyp7a1 and Cyp8b1 By Gps2 Is Medisupporting

confidence: 93%

See 1 more Smart Citation

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.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Differential Regulation Of Cyp7a1 and Cyp8b1 By Gps2 Is Medisupporting

confidence: 93%

“…Therefore, these two opposing mechanisms counteract each other and elicit a modest BA response as seen by us and others (28,29). In contrast, GW4064 triggers the SHP-dependent repression pathway only.…”

Section: Identification Of a Functional Fxr Response Element In The Hmentioning

confidence: 69%

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…29) In two human studies, increases in CYP7A1 mRNA levels were accompanied by increases in HNF-4 mRNA levels, but FXR and SHP were normally expressed. 28,29) Thus these studies suggest that the pathway via HNF-4 regulates CYP7A1 over the FXR/SHP-dependent pathway. The present results did not clearly show an increase in HNF-4 mRNA levels in rats fed CP or CIF, but revealed a tendency towards an increase in HNF-4 mRNA levels caused by CP (P ¼ 0:056), and a significant increase in HNF-4 mRNA levels in rats fed the C þ CIF diet as compared to those in rats fed the C diet.…”

Section: Discussionmentioning

confidence: 77%

“…Previously, we also found that cholestyramine up-regulates the expression of CYP7A1 independently via a LXR-or FXR-mediated pathway using the same animal model. 7) Recent research suggests that HNF-4 plays an important role in the up-regulation of CYP7A1 expression in cholestyramine-treated patients with gallstone disease 28) and in cerebrotendinous xanthomatosis patients. 29) In two human studies, increases in CYP7A1 mRNA levels were accompanied by increases in HNF-4 mRNA levels, but FXR and SHP were normally expressed.…”

Section: Discussionmentioning

confidence: 99%

Hypocholesterolemic Mechanism ofChlorella:Chlorellaand Its Indigestible Fraction Enhance Hepatic Cholesterol Catabolism through Up-Regulation of Cholesterol 7α-Hydroxylase in Rats

Shibata

Hayakawa

Egashira

et al. 2007

Bioscience, Biotechnology, and Biochemistry

View full text Add to dashboard Cite

“…These effects are partly mediated by the FXR-induced activation of the short heterodimer partner (SHP), which represses the transcription of NTCP, CYP7A1, and CYP8B1 ( Fig. 1) (Brendel et al, 2002;Gupta et al, 2002;Abrahamsson et al, 2005;Kir et al, 2012). FXR also induces bile acid detoxification via CYP3A4, SULT2A1, and UGT2B4, which further protects the hepatocyte from bile acid-induced damage (reviewed by Zollner et al, 2006).…”

Section: Bile Acid Metabolism and Its Regulationmentioning

confidence: 99%

The Role of Canalicular ABC Transporters in Cholestasis

et al. 2014

View full text Add to dashboard Cite

Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.

show abstract

Feedback regulation of bile acid synthesis in human liver: Importance of HNF-4α for regulation of CYP7A1

Cited by 47 publications

References 15 publications

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

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

Hypocholesterolemic Mechanism ofChlorella:Chlorellaand Its Indigestible Fraction Enhance Hepatic Cholesterol Catabolism through Up-Regulation of Cholesterol 7α-Hydroxylase in Rats

The Role of Canalicular ABC Transporters in Cholestasis

Contact Info

Product

Resources

About