Zonation of heme synthesis enzymes in mouse liver and their regulation by β-catenin and Ha-ras

Abstract

Cytochrome P450 (CYP) hemoproteins play an important role in hepatic biotransformation. Recently, β-catenin and Ha-ras signaling have been identified as players controlling transcription of various CYP genes in mouse liver. The aim of the present study was to analyze the role of β-catenin and Ha-ras in the regulation of heme synthesis. Heme synthesis-related gene expression was analyzed in normal liver, in transgenic mice expressing activated β-catenin or Ha-ras, and in hepatomas. Regulation of the aminolevulinate dehydratase promoter was studied in vitro. Elevated expression of mRNAs and proteins involved in heme biosynthesis was linked to β-catenin activation in perivenous hepatocytes, in transgenic hepatocytes, and in hepatocellular tumors. Stimulation of the aminolevulinate dehydratase promoter by β-catenin was independent of the β-catenin/T-cell-specific transcription factor dimer. By contrast, activation of Ha-ras repressed heme synthesis-related gene expression. The present data suggest that β-catenin enhances the expression of both CYPs and heme synthesis-related genes, thus coordinating the availability of CYP apoprotein and its prosthetic group heme. The reciprocal regulation of heme synthesis by β-catenin and Ha-ras-dependent signaling supports our previous hypothesis that antagonistic action of these pathways plays a major role in the control of zonal gene expression in healthy mouse liver and aberrant expression patterns in hepatocellular tumors.

Cooperation of structurally different aryl hydrocarbon receptor agonists and β-catenin in the regulation of CYP1A expression

“…The hepatocyte-specific knockout (KO) of the Ctnnb1 gene, encoding b-catenin, leads to a dramatic loss of the expression of perivenous marker genes such as glutamine synthetase, the model hepatic b-catenin target gene, ammonia metabolism-related genes, and especially genes encoding enzymes involved in the metabolism of drugs and xenobiotics, including many important cytochrome P450 (CYP) enzymes from families 1-3 (Benhamouche et al, 2006;Braeuning and Schwarz, 2010;Sekine et al, 2006;Tan et al, 2006). Inversely, the expression of a transgene encoding a mutant, constitutively active version of b-catenin Abbreviations: AhR, aryl hydrocarbon receptor; BHA, butylated hydroxyanisole; BNF, b-naphthoflavone; CAR, constitutive androstane receptor; CYP, cytochrome P450; DRE, dioxin response element; GS, glutamine synthetase; GST, glutathione Stransferase; 3MC, 3-methylcholanthrene; KO,knockout;tBHQ,TCDD,2,3,7, (Schreiber et al, 2011).…”

Interplay of β-Catenin with Xenobiotic-Sensing Receptors and its Role in Glutathione S-Transferase Expression

“…Similar observations (i.e. TCF binding site-independent induction, much smaller fold induction than classic Wnt target genes) were made when the induction of heme synthesis-related genes by -catenin was studied in primary mouse hepatocyte cultures [53]. Nonetheless, one cannot rule out that direct -catenin/TCF binding to the respective promoter sequences is involved in the regulation of other GSTs, or of other drug-metabolizing enzymes.…”

“…Additional data connecting -catenin signaling and hepatic GST expression stem from genetically modified mouse strains: hepatocyte-specific transgenic expression of a mutant, constitutively activated version of human -Catenin S33Y [23,53,54] induces elevated expression of GSTm protein [36]. Accordingly, the hepatocyte-specific knockout of the Ctnnb1 gene via an albumin promoter-driven Cre recombinase induces a pronounced loss of the expression of several GST isoforms [21,36].…”

“…There is evidence that Wnt/ -catenin and Ras/ERK signaling antagonistically determine the zone-specific expression of drug-metabolizing and other enzymes in mouse liver, with both signaling cascades inhibiting each other [15,20,22,36,53,91]. Thus, an inhibitory effect of -catenin on the Ras/ERK pathway might contribute to the enhanced inducibility of CAR target genes by xenobiotics in the presence of activatedcatenin.…”

Highlight: Xenobiotics and Cell Signaling

“…Cytochrome P450 enzymes (CYP) are essential players in hepatic detoxification. Not only is AhR involved in transcriptional regulation of CYP expression, but also Braeuning and Schwarz (2010) demonstrate that b-catenin and Ras signaling are antagonistic modulators of expression of enzymes involved in heme biosynthesis, i.e., the supply of cytochrome building blocks.…”