Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

Inoue, Yusuke; Yu, Aiming; Yim, Sun Hee; Ma, Xiaochao; Krausz, Kristopher W.; Inoue, Junko; Xiang, Charlie; Brownstein, Michael J.; Eggertsen, Gösta; Björkhem, Ingemar; Gonzalez, Frank J.

doi:10.1194/jlr.m500430-jlr200

Cited by 127 publications

(109 citation statements)

References 56 publications

(58 reference statements)

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“…2A). Similar trends were observed for SHP, HNF4a, and Pol II recruitment to the Cyp8b1 promoter region [which harbors the HNF4a response element (Inoue et al, 2006)] (Fig. 2B).…”

Section: Resultssupporting

confidence: 62%

“…To determine whether GW4064 alters CYP2D6 expression and activity in vivo, GW4064 or vehicle control was intraperitoneally administered to Tg-CYP2D6 mice for 5 days, and hepatic CYP2D6 mRNA and protein levels were measured by qRT-PCR and Western blot, respectively. Cyp8b1, a gene known to be downregulated by SHP (Inoue et al, 2006), was used as a positive control. The results showed that GW4064 significantly decreased both mRNA and protein expression levels of CYP2D6 by ;2-fold ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

2015

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Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme responsible for eliminating approximately 20% of marketed drugs. Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6-mediated drug metabolism. However, the factors governing CYP2D6 transcription are largely unknown. We previously demonstrated small heterodimer partner (SHP) as a novel transcriptional repressor of CYP2D6 expression. SHP is a representative target gene of the farnesoid X receptor (FXR). The objective of this study is to investigate whether an agonist of FXR, 3-(2,6-dichlorophenyl)-4-(39-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), alters CYP2D6 expression and activity. In CYP2D6-humanized transgenic mice, GW4064 decreased hepatic CYP2D6 expression and activity (by 2-fold) while increasing SHP expression (by 2-fold) and SHP recruitment to the CYP2D6 promoter. CYP2D6 repression by GW4064 was abrogated in Shp(2/2);CYP2D6 mice, indicating a critical role of SHP in CYP2D6 regulation by GW4064. Also, GW4064 decreased CYP2D6 expression (by 2-fold) in primary human hepatocytes, suggesting that the results obtained in CYP2D6-humanized transgenic mice can be translated to humans. This proof of concept study provides evidence for CYP2D6 regulation by an inducer of SHP expression, namely, the FXR agonist GW4064.

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“…2A). Similar trends were observed for SHP, HNF4a, and Pol II recruitment to the Cyp8b1 promoter region [which harbors the HNF4a response element (Inoue et al, 2006)] (Fig. 2B).…”

Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

2015

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“…The rescued embryos fail to express the correct profile of liver-specific genes, indicating an additional role for HNF-4␣ in the terminal differentiation of hepatocytes (17). In the adult mouse, Hnf4a expression has been reported in liver, kidney, intestine, stomach, and pancreas (12,13), where HNF-4␣ is responsible for the regulation of genes involved in processes such as insulin secretion (11), gluconeogenesis (18), bile acid synthesis (19), and lipid metabolism in adult humans (20).…”

mentioning

confidence: 99%

The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development

Harries

Locke²,

Shields³

et al. 2008

Diabetes

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OBJECTIVE-Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype.RESEARCH DESIGN AND METHODS-We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations.RESULTS-HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4 -6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P ϭ 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P Ͻ 0.00001).CONCLUSIONS-We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.

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“…A human genetic deficiency in HNF4α expression in pancreatic β-cells causes the disease MODY-1 (maturity onset diabetes of the young-1). In adult liver, HNF4α regulates transcription of a large number of genes involved in liver-specific functions, such as bile acid and apolipoprotein synthesis, coagulation, urea synthesis, drug metabolism and gluconeogenesis [6][7][8][9][10][11]. The absence of HNF4α expression in adult mice results in increased mortality [6], thus indicating that HNF4α controls constitutive expression of genes that are essential for liver function.…”

Section: Hnf4αmentioning

confidence: 99%

Role of HNF4α in the superinduction of the IL-1β-activated iNOS gene by oxidative stress

Gonzalez

2006

Biochemical Journal

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IL-1β (interleukin-1β) treatment of hepatocytes results in an NF-κB (nuclear factor-κB)-mediated activation of the iNOS (induced nitric oxide synthase) gene, and this increase in gene expression is further augmented by oxidative stress. Oxidative stress alone has no influence on the iNOS promoter, therefore indicating that the promoter needs to be primed by NF-κB. In this issue of the Biochemical Journal, Guo et al. extend their earlier work, showing that HNF4α (hepatocyte nuclear factor 4α) mediates the superinduction of iNOS observed by co-treating cells with IL-1β plus H2O2. A specific phosphorylation by p38 kinase at Ser-158 of HNF4α results in increased binding of HNF4α to the iNOS promoter, leading to enhanced transcription. The study by Guo et al. is the first to show definitively that HNF4α can be modulated to differentially activate specific genes. However, issues remain to determine the functional significance in vivo of the elevated iNOS activity, and the mechanism that governs the specificity of HNF4α towards the iNOS promoter element as compared with many other HNF4α target genes in the hepatocyte.

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Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

Cited by 127 publications

References 56 publications

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development

Role of HNF4α in the superinduction of the IL-1β-activated iNOS gene by oxidative stress

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