PPAR Isoforms

II. PPARy Structure and Function 1. PPAR Isoforms—Molecular Biology and Tissue Expression... 

The PPARs constitute a family of three nuclear receptors that have important roles in physiological lipid and glucose metabolism. Converse, dysregulation of the PPARs has been associated with pathophysiological conditions such as hyperlipidemia, insulin resistance and coronary artery disease. There are three PPAR isoforms -PPARa, PPARy and PPARS (also termed PPARP). All PPARs are expressed in cardiovascular tissues and in addition to their known metabolic actions they exhibit distinct functions. While the expression of PPARa and PPARP/8 is surprisingly high in the heart, PPARy expression is very low and does not appear to play an important role in the heart. Since Chapter 11 in this book is dedicated to the well-established role of the PPARs in metabolic diseases, we will focus in this chapter on the role of P PA Ra in cardiac diseases. 

PPARs belong to a family of nuclear transcription factors that heterodimerize with retinoid X receptors (RXR) and function in a ligand-dependent manner [5]. They can activate transcription through binding peroxisome proliferator activated receptor response elements (direct repeat of AGGTCA spaced by one nucleotide). To date, three different PPAR isoforms a, 5/p, and y (and splice variants) have been identified that are encoded by separate genes. The tissue-specific expression pattern of these transcription factors is indicative of their function in those tissues [6]. 

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The three PPAR isoforms (a, p/8, and y) are known to occur in mammalian tissues. In response to specific agonists, these receptors form dimers and translocate to the nucleus, where they act as agonist-dependent transcription factors and regulate gene... 

CLA has also been shown to be a good ligand of nuclear receptors called peroxisome proliferator activated receptors (PPAR) (45). CLA is specifically active on two PPAR isoforms, a and y. The isoform a is found mainly in liver and functions as a transcription factor for many enzymes involved in fatty acid oxidation and particularly, peroxisomal 3-oxidation. We recently detected peroxisomal 3-oxidation products of CLA and metabolites in rat tissues and in humans (unpublished data). This finding would prompt the question whether CLA, as a good substrate for peroxisomal 3-oxidation, has any effect on peroxisomal P-oxidation. Indeed, it has been reported that induction of several key enzymes of peroxisomal P-oxidation was through the activation of PPARa by CLA (45). 

In 1990, a reeeptor that mediates the effects of PPs, the peroxisome proliferator activated reeeptor alpha, PPARa, was identified in motrse liver. The isolation of htrman PPARa arrd other isoforms of PPAR (P and y) both from roderrts and humans followed on rapidly. " In rats and mice, PPARa is highly expressed in the liver, whereas other forms such as PPARy are expressed predominantly in fatty adipose tissue and in the immune system. This tis-sue-specifie pattern of expression implies a differerrt ftmetion for the PPAR isoforms both in normal tissue homeostasis and in resportse to dmgs and toxicants. 

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

The expression of all three PPAR isotypes peaks in the rat central nervous system between days 13.5-18.5 of gestation, and while expression of both PPARa and PPARy decline post-natally, expression of PPARS remains high (except for the retina, where all three isoforms are expressed in the adult rodent). An important role for PPARS in CNS development is underscored by the occurrence of defective myelination in the PPARS-null mouse. 

Sleep A class of drug that were developed as insulin-sensitizing agents and are currently used for the treatment of type 2 diabetes. They have been shown to bind to and activate the y isoform of the PPARs, which is particularly expressed in adipocytes, and appear to function in part by stimulating the release of... 

A study using human hepatoma cells expressing PPARa, (3/8, or y showed that the DEHP metabolite, MEHP, activated all three isoforms of PPAR in a dose-related fashion, but DEHP did not (Lapinskas and Corton 1997). In addition, the metabolite 2-ethylhexanoic acid was isoform-specific since it activated PPARa but not p/S or y. Similar findings were observed by Maloney and Waxman (1999) who showed that MEHP (but not DEHP) activated mouse and human PPARa and PPAR8, while EHA activated mouse and human PPARa only, and at much higher concentrations. These data are consistent with observations in vivo and in vitro indicating that the toxicity of DEHP is due mainly to MEHP. 

The mammalian PPAR family also includes a third isoform, referred to as PPAR8 (22), which is also known as PPAR(3 or NUC1 and is expressed in many different cell types and tissues (13, 22). Specific target genes, natural ligands, and bona fide physiologic roles for PPARS remain to be defined. 

The first PPAR was reported by Issemann and Green30 in rodents. To date, three distinct PPARs, encoded by three distinct genes have been identified PPARa, PPAR/3, and PPARy. These isoforms have different tissue distributions, with PPARa expressed primarily in liver, heart and kidney, PPARy in brown and white adipose tissues, and PPAR/3 (also known as 8) is more ubiquitously expressed, but most abundant in the central nervous system14,17,35. The role of each isoform is beyond the scope of this review as fibrate drugs are mainly PPARa-ligands14, only this form will be examined in detail here. Nevertheless, it should be mentioned that isoforms of the PPAR family have now been cloned from Xenopus laevis, a number of mammals49,50, as well as in some fish species1. 

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