Shared Regulation of <i>UGT1A7</i> by Hepatocyte Nuclear Factor (HNF) 1α and HNF4α

Ehmer, Ursula; Kalthoff, Sandra; Lankisch, Tim O.; Freiberg, N.; Manns, Michael P.; Strassburg, Christian P.

doi:10.1124/dmd.109.030403

Cited by 15 publications

(6 citation statements)

References 43 publications

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“…HNF1␣ was found to activate the UGT1A7 promoter in KYSE70, Caco2, HepG2, and HEK293 cell lines. HNF4␣ coactivated UGT1A7 expression with HNF1␣ in KYSE70 cells (163) and stimulated the UGT1A7 promoter alone in HepG2 cells (163) in the proximal promoter, one of which is essential while the others have an enhancing function (163). HNF4␣ functions via two HNF4 sites in the proximal promoter that appear to act cooperatively (163).…”

Section: Constitutive Expression Of Ugt1 Family Genesmentioning

confidence: 99%

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms

Meech

McKinnon

et al. 2019

Physiological Reviews

250

168

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UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently; these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.

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Section: Constitutive Expression Of Ugt1 Family Genesmentioning

confidence: 99%

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms

Meech

McKinnon

et al. 2019

Physiological Reviews

250

168

View full text Add to dashboard Cite

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“…Interestingly, the HNF1AE was included in the region of H3K4me2 enrichment. Numerous studies have demonstrated that, as an evolutionarily conserved transcription factor, HNF1A can mediate the transcriptional activation of UGTs, including UGT1A1, 1A3, 1A4, 1A9, and UGT2B7 (Bernard et al, 1999;Ishii et al, 2000;Toide et al, 2002;Gregory et al, 2004;Odom et al, 2004;Gardner-Stephen and Mackenzie, 2007;Ramírez et al, 2008;Li et al, 2009a;Ehmer et al, 2010). Additionally, H3K4me2 is generated by the histone methyltransferase MLL1; however, due to a lack of intrinsic DNA-binding activity, histone-modifying enzymes need to be recruited to genomic DNA by other factors, such as transcription factors.…”

Section: Downloaded Frommentioning

confidence: 99%

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

et al. 2017

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Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression. We further showed that the transcription factor hepatocyte nuclear factor 1 (HNF1A) affects histone modifications around the locus. In particular, we demonstrated that by recruiting HNF1A the cofactors mixed-lineage leukemia 1, the transcriptional coactivator p300, and nuclear receptor coactivator 6 aggregate at the promoter, thereby regulating histone modifications and subsequent UGT1A1 expression. In this study, we proposed new ideas for the developmental regulation of metabolic enzymes via histone modifications, and our findings will potentially contribute to the development of age-specific therapies.

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“…17) The expression levels of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A6, UGT1A9, and UGT2B7 have been reported to be regulated by HNF-4α. [18][19][20][21][22] However, HNF-4α induction did not alter the expression of CYP2D6. This phenomenon may indicate the existence of other regulators of CYP2D6.…”

Section: Discussionmentioning

confidence: 99%

Human Hepatocarcinoma Functional Liver Cell-4 Cell Line Exhibits High Expression of Drug-Metabolizing Enzymes in Three-Dimensional Culture

Kato

Shigemoto

Akiyama

et al. 2014

Biological & Pharmaceutical Bulletin

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The expression levels of CYP and uridine diphosphate-glucuronosyl transferase (UGT) are lower in hepatocellular carcinoma cell lines than in human primary hepatocytes. However, a functional liver cell (FLC)-4 cell line that has a greater capacity to secrete liver-specific proteins than other hepatocellular carcinoma cells has recently been established. A three-dimensional culture using Engelbreth-Holm-Swan (EHS) gel induces the secretion of liver-specific proteins via the induction of hepatocyte nuclear factor-4α (HNF-4α). The aim of this study was to evaluate the mRNA expression of the enzymes CYP and UGT in FLC-4 and HepG2 cells in monolayer and three-dimensional cultures using EHS gel. The mRNA levels of HNF-4α, albumin, pregnane X receptor (PXR), constitutive androstane receptor (CAR), CYPs (1A2, 2E1, 2C8, 2C9, 2C19, 2D6, and 3A4) and UGTs (1A1, 1A6, 1A9, and 2B7) were determined using real-time reverse transcription (RT) PCR. In a monolayer culture, the mRNA expression levels of HNF-4α, albumin, PXR, CAR, CYPs (2E1, 2C9, 2C19, 2D6, and 3A4) and UGTs (1A1, 1A6, and 1A9) were higher in FLC-4 cells than in HepG2 cells. In FLC-4 cells, the mRNA expression levels of HNF-4α, albumin, PXR, CAR, CYPs (2E1, 2C8, 2C19, and 3A4) and UGTs (1A1, 1A6, 1A9, and 2B7) significantly increased in three-dimensional culture. FLC-4 cells cultured in EHS gel showed significantly increased expression levels of CYPs and UGTs. The results of this study suggest that human hepatocellular carcinoma FLC-4 cells cultured in EHS gel show potential for use in studying in vitro drug metabolism.Key words CYP; uridine diphosphate-glucuronosyl transferase; expression; functional liver cell; threedimensional culture Human hepatocellular carcinoma cell lines (e.g. HepG2, Hep3B, and HuH7) are widely used to study drug metabolism and toxicology in vitro. The expression levels of CYP and uridine diphosphate-glucuronosyl transferase (UGT) in hepatocellular carcinoma cell lines are known to be lower than those in human primary hepatocytes. 1) However, under typical culture conditions, human primary hepatocytes are unable to sustain stable hepatic functions, such as production of drugmetabolizing enzymes.2) Therefore, hepatic microsomes are usually used in in vitro experiments related to drug metabolism. Functional liver cell (FLC) lines have been established from resected liver tumors of Japanese patients. These cells synthesized and secreted human albumin, alpha-fetoprotein, and other proteins in vitro. 3)Many reports have shown that the differentiation status of primary culture hepatocytes could be enhanced by threedimensional culture.4,5) Engelbreth-Holm-Swan (EHS) gel, derived from mouse EHS sarcoma, induces the expression of hepatocyte nuclear factor-4α (HNF-4α).6) HNF-4α has been reported to play a significant role in the regulation of many genes expressed in the liver and to trans-activate the human pregnane X receptor (PXR) gene. 7,8) Human PXR is known to be a transcriptional regulator of genes encoding drug-metabolizing enzymes, including C...

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Shared Regulation of UGT1A7 by Hepatocyte Nuclear Factor (HNF) 1α and HNF4α

Cited by 15 publications

References 43 publications

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms

The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

Human Hepatocarcinoma Functional Liver Cell-4 Cell Line Exhibits High Expression of Drug-Metabolizing Enzymes in Three-Dimensional Culture

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