Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor.

Abstract

Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Unsaturated fatty acids induce peroxisomal proliferation and lower blood triglyceride levels (1-3). Similar effects are evoked by a number of man-made compounds which are either considered for therapy of hyperlipidemia-e.g., clofibric acid, nafenopin, WY-14,643, or sulfur-substituted fatty acids-or are in use as industrial plasticizers (4-6). The steroid dehydroepiandrosterone (DHEA) also induces peroxisomal proliferation but increases blood triglyceride and cholesterol levels (7,8). Two main hypotheses have been developed to explain the complex response of peroxisomal proliferation to this wide variety of inducers. According to one theory the intracellular accumulation of fatty acids is the key stimulus for triggering peroxisomal proliferation (4, 9). The other theory postulates the involvement of a receptor protein (4, 10) and an as-yet-unknown intracellular messenger-e.g., the ligand for this receptor.The latter idea gained substantial support from the discovery of mouse peroxisome proliferator-activated receptor (mPPAR), a member of the steroid nuclear receptor superfamily (11,12). The gene encoding PPAR belongs to a number of genes cloned in the last few years by means of their homology with steroid receptors. In general, ligands or physiologically occurring activators have been identified for only a few of these so-called orphan receptors (13-15). In the case of mPPAR, transactivation studies using chimeric proteins composed of the putative ligand-binding domain of the novel receptor and DNA-binding domains of known steroid receptors showed that mPPAR could be activated by peroxisome proliferators (11). However, the identity ofthe ultimate ligand of the receptor protein, the nature of physiological activators, and how the receptor might relate to the concept of fatty acids as inducers of peroxisomal proliferation remain unclear.We now describe the cloning from rat liver of a gene homologous to that encoding mPPAR.

Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression.

“…direct repeats of the sequence TGACCT, the consensus binding site for several members of the nuclear hormone receptor superfamily. Signal transduction by peroxisome proliferators is apparently mediated through distinct ligandactivated receptors, collectively known as peroxisome proliferator-activated receptors (PPARs), that belong to this family of transcription factors (10)(11)(12)(13). Recently, the mouse PPAR (mPPAR) has been shown to bind cooperatively to the AOx PPRE through heteromerization with the 9-cis-retinoic acid receptor, RXRa (14).…”

Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ

“…Recent evidence suggests that FAs can rapidly modulate the transcription of genes involved in their own metabolism (2)(3)(4). Insight into the mechanism underlying some of these effects of FAs on gene expression was provided by the identification of several closely related orphan nuclear receptors, termed peroxisome proliferator-activated receptors (PPARs), that are activated by micromolar concentrations of a variety of FAs and FA analogues, including the hypolipidemic fibrate class of drugs (5)(6)(7)(8). Three mammalian PPARs, designated PPAR␣, ␥, and ␦ (9, 10), and three Xenopus laevis PPARs, designated xPPAR␣, -␤, and -␥ (11), have been isolated.…”

Down-regulation of rat mitochondrial branched-chain 2-oxoacid dehydrogenase kinase gene expression by glucocorticoids

“…The latter hormone enhances the transcription of PPARα ; however, the level of acyl-CoA oxidase mRNA targeted by PPARα is not induced by dexamethasone in the absence of ligands such as WY-14643 [39,41]. These studies depict interesting interplays between metabolic hormones, liganddependent transcription factors and the target gene that encodes the enzyme involved in catabolism of the potential ligand fatty acids.…”

“…The discovery of retinoic acid receptors, retinoid X receptors [38] and peroxisome-proliferator-activated receptors (PPARs) [39][40][41] has led to the concept that nutrients play an important role in activating ligand-dependent transcription factors. For instance, retinoic acid and retinoid X receptors are activated by retinoic acids derived from vitamin A, and PPARs are activated by hypolipidaemic drugs or physiologically occurring ligands such as arachidonic acid and linoleic acid.…”

“…For instance, retinoic acid and retinoid X receptors are activated by retinoic acids derived from vitamin A, and PPARs are activated by hypolipidaemic drugs or physiologically occurring ligands such as arachidonic acid and linoleic acid. PPARα [39][40][41], which in turn activates several target genes involved in fatty acid catabolism, is subject to regulation by glucocorticoids [39,42].…”