Carcinogenesis

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Carcinogenesis, Vol. 20, No. 3, 369-372, March 1999
© 1999 Oxford University Press

Accelerated Papers

The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs

N.J. Woodyatt, K.G. Lambe, K.A. Myers, J.D. Tugwood and R.A. Roberts¹

Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield SK10 4TJ, UK

	Abstract

Top Abstract Introduction Materials and methods Results and discussion References

 
Peroxisome proliferators (PP) cause peroxisome proliferation, associated with rodent hepatocyte growth perturbation and hepatocarcinogenesis. However, in humans this class of non-genotoxic carcinogens does not appear to have the same adverse effects. The peroxisome proliferator-activated receptor (PPAR) mediates the effects of PPs in rodents via peroxisome proliferator response elements (PPREs) upstream of PP-responsive genes such as acyl coenzyme A oxidase (ACO). When the human ACO promoter was cloned previously, it was found to be active and to contain a consensus PPRE (–1918 AGGTCA C TGGTCA –1906). To confirm and extend those original findings, we isolated a 2 kb genomic fragment of the ACO gene promoter from a human liver biopsy and used it to create a ß-galactosidase reporter gene plasmid. The human ACO promoter reporter plasmid was added to both Hepa1c1c7 and NIH 3T3 cells together with a plasmid expressing mPPAR and assessed for its ability to drive PP-mediated gene transcription. The human ACO promoter fragment was inactive, unlike the equivalent rat ACO promoter fragment used as a positive control. The PPRE within our cloned fragment of the human ACO promoter differed at three positions (5'-AGGTCA G CTGTCA-3') from the previously published active human ACO promoter. Next, we studied the frequency of the inactive versus the active human PPRE within the human population. Using a PCR strategy, we isolated and analysed genomic DNA fragments from 22 unrelated human individuals and from the human hepatoma cell line HepG2. In each case, the PPRE contained the inactive sequence. These data show that the human ACO gene promoter found in a sample human population is inactive. This may explain at the genomic level the lack of response of humans to some of the adverse effects of the PP class of non-genotoxic hepatocarcinogens.

Abbreviations: ACO, acyl coenzyme A oxidase; ApoA1, apolipoprotein A-1; CYP4A1, cytochrome p450 4A1; PP, peroxisome proliferator; PPAR, peroxisome proliferator-activated receptor ; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor.

	Introduction

Top Abstract Introduction Materials and methods Results and discussion References

 
Peroxisome proliferators (PPs) constitute a diverse class of non-genotoxic chemicals associated with rodent hepatocarcinogenesis. This class includes hypolipidaemic fibrate drugs, clingwrap/medical tubing plasticizers, pesticides and solvents (reviewed in refs 1–3). Both in vivo and in vitro, PPs induce rodent hepatocyte DNA synthesis and suppress apoptosis (reviewed in refs 4,5). In addition to altering rat and mouse hepatocyte growth regulation, PPs cause peroxisome proliferation, associated with induction of enzymes of the fatty acid ß-oxidation pathway, typified by acyl coenzyme A oxidase (ACO) (reviewed in ref. 6). PPs mediate their biological responses via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) (7). Transgenic mice lacking PPAR do not undergo hepatic peroxisome proliferation, ACO induction, liver enlargement or tumourigenesis in response to PP administration (8,9). PPAR heterodimerises with the retinoid X receptor (RXR) (reviewed in ref. 10) and the heterodimer binds to DNA at peroxisome proliferator response elements (PPREs) upstream of genes associated with response to PPs such as ACO and cytochrome P4504A1 (CYP4A1) (11–13). These PPREs comprise a direct repeat of a consensus sequence separated by one nucleotide (a direct repeat or the direct repeat 1 element) (11,14,15).

Humans appear to be refractory to the adverse effects of PPs (reviewed in ref. 1). In human hepatocytes in vitro there is no detectable peroxisome proliferation, induction of S phase nor suppression of apoptosis in response to a diverse range of PPs. In addition, there is no increase in the incidence of hepatocarcinogenesis seen in follow-up studies of patients treated with fibrate hypolipidaemic drugs (16–18). Since humans are exposed to PPs therapeutically (19) and in the environment (20), it is important to determine whether any health risk exists.

Since the adverse effects of PPs seen in rodents such as peroxisome proliferation and ACO induction are thought not to occur in humans, it was perhaps surprising when a 5' fragment of the human ACO promoter was cloned and found to be active in reporter gene assays (21,22). The PPRE was located within a 203 bp fragment between bases –2015 and –1812 and was identified as 5'-AGGTCA C TGGTCA-3' between –1918 and –1906. We wished to confirm and extend those reports to understand further the molecular basis for the apparent lack of human response to the adverse effects of PPs. Here, we show that the human ACO gene promoter found in a sample human population is inactive, perhaps explaining at the genomic level the lack of response of humans to some of the adverse effects of the PP class of non-genotoxic hepatocarcinogens.

	Materials and methods

Top Abstract Introduction Materials and methods Results and discussion References

 
Isolation and sequencing of the human ACO gene promoter
Genomic DNA was extracted from a human liver biopsy as described in Ausubel et al. (23). Using oligonucleotides 5'-TAT TCT TGT AAT TCT CGT GT (717) and 5'-AGC TGG CAG CGA AGT AA (ACOU1), a –2072/+43 fragment of the human ACO (hACO) promoter was amplified by PCR using PfuI polymerase (Stratagene). The major product of 2 kb was gel isolated, cloned into pCR2.1 (Invitrogen) and sequenced. To sequence multiple human ACO PPREs, genomic DNA was extracted from 20 human blood samples, three human liver samples and a HepG2 cell pellet. Bases –2072 to –1649 were PCR amplified from human genomic DNA using primers 717b (5'-TATTCTTGTAATTCTCGTGTAAAT-3') and ACO PCR1 (5'-TCTGTGTAATACTATGACTTTGGTT-3'). PCR products were analysed by agarose gel electrophoresis and dilutions of the PCR products used as template in two further reactions, one with primers 717b and ACO PCR2 (5'-ACCTCAGGATCCTCATTTGTCTT-3') (N1 reactions) and the other with ACO DN (5'-AAATTTAGCTCTTCATCTAAGTC-3') and ACO PCR1 (N2 reactions). The N1 and N2 reaction products were sequenced using primers ACO DN and ACO PCR2, respectively.

Plasmid construction
Both the rat (r) and human (h) promoter reporter plasmids were derived from pAPOA1ß.neo (a gift from C.Summers, Zeneca Pharmaceuticals) by replacement of the apolipoprotein A-1 (ApoA1) promoter. prACO(–1273/+20)ßgal.neo was derived by insertion of the previously described rat ACO promoter fragment (11). phACO(–2072/+43)ßgal.neo was derived by insertion of the –2072/+43 fragment of the human ACO promoter. mPPAR (7) and mRXR (a gift from Pierre Chambon) were subcloned into pcDNA3 for use in the reporter gene assays as described previously (24).

Transient transfection and reporter gene assays
Growth and lipofectin-mediated transfection were as described previously (11,24). For Hepa1c1c7 cells, each plate (~3x10⁵ cells) was transfected with 0.2 µg mPPAR expression vector, 0.1 µg reporter plasmid and 0.5 µg luciferase expression vector (transfection control). For NIH 3T3 cells, transfections were as described above but included 0.2 µg of mRXR expression vector. Wyeth-14,643 (ChemSyn, Junction City, OR) was used as the PPAR activating ligand.

	Results and discussion

Top Abstract Introduction Materials and methods Results and discussion References

 
To confirm and extend reports that the human ACO promoter is active, we isolated genomic DNA from a human liver biopsy and cloned the 5' promoter region of the human ACO gene (–2072/+43); this fragment was placed in a reporter plasmid upstream of a ß-galactosidase reporter gene (phACOßgal.neo). To confirm transcriptional activity of this human ACO promoter, reporter gene assays were conducted in Hepa1c1c7 cells as described previously (11) using prACOßgal.neo, a comparable reporter plasmid containing the rat ACO promoter (–1273/+20), as a positive control. There was very little reporter gene expression driven by the human ACO promoter in the absence of ligand as determined by ß-galactosidase activity (Figure 1A). In addition, there was no significant induction of reporter gene expression relative to control on addition of the PPAR ligand Wyeth-14,643. This was in contrast to ß-galactosidase expression driven by the rat ACO promoter, where constitutive expression could be detected and addition of Wyeth-14,643 gave a 3-fold induction (Figure 1A). To confirm these data, similar experiments were repeated in a second cell line, NIH 3T3, selected principally since its tissue origin is far removed from the hepatic parenchyma but also for ease of transfection (Figure 1B). Again, Wyeth-14,643 gave an induction of rat ACO promoter-driven reporter gene expression whereas there was neither constitutive nor inducible expression from the human ACO promoter. Thus, the human ACO promoter fragment was inactive, unlike the equivalent rat ACO promoter fragment.

View larger version (26K): [in this window] [in a new window]   Fig. 1. Transcriptional activity of the rat but not the human ACO promoter in (A) Hepa1c1c7 and (B) NIH 3T3 cells. Hepa1c1c7 cells were transfected with 0.2 µg mPPAR expression vector, 0.1 µg reporter plasmid and 0.5 µg luciferase expression vector (transfection control). NIH 3T3 cells were transfected as above with the inclusion of 0.2 µg mRXR expression vector. Wy-14,643 (100 µM) was used as the PPAR activating ligand. After 48 h, ß-galactosidase activity was determined and normalized for luciferase activity. Data points are the means of three independent determinations.

 
To further evaluate the properties of the PPRE within our cloned human ACO promoter, we sequenced a fragment of the promoter (–2072/–1629), including the PPRE. This inactive human PPRE differed at four positions from the active rat ACO PPRE and also at three positions from the previously published (21) active human ACO promoter (Figure 2). One possibility was that there are polymorphisms among the human population at the ACO PPRE, raising the question of inter-individual variation in response to PPs. To investigate the distribution of the active versus the inactive PPRE in the human population, we isolated genomic DNA from a further 22 unrelated humans. In addition, we isolated genomic DNA from the human hepatoma cell line HepG2, since this cell line has been used to model the lack of human response to PPs in vitro (25), sometimes on the premise that the intrinsic ACO promoter is active in this human cell line (26). Using a nested PCR-based strategy (Figure 2B), the ACO promoter was sequenced from –2019 to –1756, including the PPRE at –1918 to –1906. In each case, including HepG2 cells, the PPRE contained the inactive sequence (Figure 2C). These data show that the human ACO gene promoter in a sample human population is incapable of driving PP-mediated gene expression. Both the human PPRE described herein and that published previously (21) differ in sequence and location from the rat ACO PPRE described in 1992 (11; Figure 3). In addition, the sequence described herein differs from the previously published human ACO PPRE at 3 bp (Figure 3).

View larger version (33K): [in this window] [in a new window]   Fig. 2. Sequence of the human ACO gene promoter and alignment of the PPRE with the published rat and human sequences (11,21). (A) Part of the 5' region of the human ACO promoter was sequenced in phACOßgal.neo. Numbers quoted are relative to the transcriptional start site at +1. Bold underlined text indicates the PPRE consisting of the sequence AGGTCA G CTGTCA (–1918 to –1906). The sequence has been submitted to EMBL (accession no. AJ011352). (B) A schematic outlining the strategy used to analyse the human ACO PPRE sequence in multiple genomic DNA samples. Genomic DNA was extracted from 20 human blood samples, three human liver samples and a HepG2 cell line pellet. (C) All sequences analysed (23 humans plus HepG2 cell line) were identical at the PPRE. Base differences between the reported human ACO PPRE (21) and our sequence data are shown in bold.

 

View larger version (23K): [in this window] [in a new window]   Fig. 3. Schematic of the sequence of the previously published human ACO PPRE (21) and its position relative to the transcription initiation site (+1) and a comparison with the rat ACO PPRE (11) and the human ACO PPRE described herein. The PPREs in the two species are orientated in opposite directions relative to the transcription start site at +1.

 
The lack of activity of the human ACO gene promoter is perhaps not surprising since this gene appears not to be activated in human hepatocytes in response to PPs either in vivo or in vitro (reviewed in ref. 1). Likewise, other genes associated with the adverse effects of PPs in rodents, such as CYP4A1, are not up-regulated in human hepatocytes (reviewed in ref. 1). The data presented here on the human ACO promoter suggest that this absence of up-regulation in humans may be attributed to the absence of a functional PPRE in the genes associated with rodent peroxisome proliferation.

Although all the evidence suggests that there are no adverse effects of PPs in humans, they clearly can respond to PPs since the ability of hypolipidaemic fibrate PPs to alter human lipid metabolism (27) forms the basis of their clinical use. Fibrates such as ciprofibrate and clofibrate (28,29) modulate intracellular and extracellular lipid metabolism via alterations in the major high density apolipoproteins, apoAI and apoAII. In addition, plasma triglycerides are reduced via induction of lipoprotein lipase and reduction of apoCIII (reviewed in refs 19,30). Thus, species differences in gene expression in response to PPAR ligands may be at the level of gene promoter sequence, rather than dictated by intracellular concentration of activated PPAR. Interestingly, the ApoA1 gene promoter provides a precedent for species differences in sequence and activity of PPREs. The rat ApoA1 gene promoter is non-responsive to fibrates, unlike its human homologue, and studies of the PPREs show this to be due to three nucleotide differences between the rat and the human promoter (31).

In addition to a difference in the ACO promoter between species, there may be additional factors that dictate a lack of response of humans to PPs (32). Undoubtedly, human hepatocytes express lower levels of functional PPAR when compared with rodents (33–35). Recent evidence (N.Macdonald and R.A.Roberts, unpublished data) supports a quantitative hypothesis wherein PPAR expression in humans is too low for transcriptional regulation of the full battery of genes associated with the adverse effects of PPs seen in rodents. The data presented herein suggest that the human ACO gene promoter is inactive in most individuals, providing a molecular basis for the observed species differences in response to PPs at the level of ACO gene induction. Further work is required to evaluate whether this provides a common mechanism to explain a lack of human response to the other adverse effects of PPs seen in rodents.

	Notes

 
¹ To whom correspondence should be addressed Email: ruth.roberts{at}ctl.zeneca.com

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Received October 14, 1998; revised November 11, 1998; accepted November 11, 1998.

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