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I Issemann

Publications and source records attributed to I Issemann.

9 recordsLinked to original sources
PubMed1993

The retinoid X receptor enhances the function of the peroxisome proliferator activated receptor.

The peroxisome proliferator activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of non-genotoxic rodent hepatocarcinogens termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl-CoA oxidase that is elevated about 10-fold in the liver of treated rodents. We have shown previously that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat acyl-CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. These results therefore suggest that retinoids may modulate the action of peroxisome proliferators.

Acyl-CoA Oxidase↗
PubMed1993

The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs.

The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about tenfold in the livers of treated rodents. We have previously shown that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat peroxisomal acyl CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. We have also shown that a variety of hypolipidaemic drugs and fatty acids can activate PPAR. This supports the suggestion that the physiological role of PPAR is to regulate fatty acid homeostasis, and provides further evidence that PPAR is the target of the fibrate class of hypolipidaemic drugs. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR.

Animals↗
PubMed1992

The mouse peroxisome proliferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene.

Peroxisome proliferators are a diverse group of chemicals, including several hypolipidaemic drugs, that activate a nuclear hormone receptor termed the peroxisome proliferator activated receptor (PPAR). The peroxisomal enzyme acyl CoA oxidase (ACO) is the most widely used marker of peroxisome proliferator action. We have examined the 5' flanking region of the rat ACO gene for sequences that mediate the transcriptional effect of peroxisome proliferators and have identified an element located 570 bp upstream of the ACO gene that confers responsiveness to the hypolipidaemic peroxisome proliferator Wy-14,643. This peroxisome proliferator response element (PPRE) contains a direct repeat of the sequence motifs TGACCT and TGTCCT and binds PPAR. These data therefore indicate an important role of PPAR in mediating the action of peroxisome proliferators including the induction of ACO.

Acyl-CoA Oxidase↗
PubMed1992

The molecular mechanism of peroxisome proliferator action: a model for species differences and mechanistic risk assessment.

An increasing number of chemicals that produce tumours in rodent bioassays belong to the non-genotoxic class of carcinogens. There are no suitable tests for these carcinogens and our understanding of their mechanism of action is poor. Importantly, assessment of their potential hazard to man is usually difficult without extensive research. Peroxisome proliferators (PP) are a diverse group of rodent non-genotoxic carcinogens that include hypolipidemic drugs, plasticizers and herbicides. We have reported previously the cloning of a member of the nuclear hormone receptor superfamily and, through the use of chimeric receptors, discovered that it could be activated by PPs. The receptor is therefore termed the PP activated receptor (PPAR). The most widely used marker of PP action is the peroxisomal beta-oxidation enzyme acyl CoA oxidase (ACO). Interestingly, it has been speculated that the hydrogen peroxide produced as a result of ACO activity could lead to DNA damage and tumorigenesis. We have now demonstrated that PPAR recognizes a specific PP response element (PPRE) located in the ACO gene promoter and that the response is dependent upon the presence of receptor and the addition of the PP Wy-14,643. These data therefore support a model in which the mechanism of PP action is mediated by PPAR in a manner similar to that of steroid hormone action. Learning more about the function of PPAR offers a unique opportunity to understand the mechanism of action of some non-genotoxic carcinogens. Furthermore, this knowledge when combined with comparison of receptor expression between rodents and man will be important in providing a framework for a new threshold model of risk assessment based upon receptor-mediated carcinogenesis.

Acyl-CoA Oxidase↗
PubMed1991

Cloning of novel members of the steroid hormone receptor superfamily.

We describe the cloning of four novel members of the steroid hormone receptor superfamily of ligand-activated transcription factors. Using chimaeric receptors we demonstrate that one of the receptor homologues is activated by the diverse peroxisome proliferator class of rodent hepatocarcinogens that includes hypolipidaemic drugs and industrial plasticisers. The identification of this receptor homologue should help elucidate the hypolipidaemic mechanism of these compounds and aid our evaluation of their potential carcinogenic risk to man.

Amino Acid Sequence↗
PubMed1990

Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.

We have cloned a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The receptor homologue is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes. Identification of a peroxisome proliferator-activated receptor should help elucidate the mechanism of the hypolipidaemic effect of these hepatocarcinogens and aid evaluation of their potential carcinogenic risk to man.

Amino Acid Sequence↗