Peroxisome proliferator-activated receptor (PPAR) ␣, PPAR␥, and retinoid acid receptor-related orphan receptor (ROR) ␣ are members of the nuclear receptor superfamily of ligand-activated transcription factors. Although they play a key role in adipocyte differentiation, lipid metabolism, or glucose homeostasis regulation, recent studies suggested that they might be involved in the inflammation control and especially in the modulation of the cytokine production. This strongly suggests that these transcriptional factors could modulate the deleterious effects of interleukin-1 (IL-1) on cartilage. However, to date, their presence in cartilage has never been investigated. By quantitative reverse transcription-polymerase chain reaction, Western blot, and immunocytochemistry analysis, we demonstrated, for the first time, the presence of PPAR␣, PPAR␥, and ROR␣ in rat cartilage, at both mRNA and protein levels. Comparatively, the PPAR␣ mRNA content in cartilage was much lower than in the liver but not significantly different to that of the adipose tissue. PPAR␥ mRNA expression in cartilage was weak, when compared with adipose tissue, but similar to that found in the liver. ROR␣ mRNA levels were similar in the three tissues. mRNA expression of the three nuclear receptors was very differently modulated by IL-1 or mono-iodoacetate treatments. This indicates that they should be unequally involved in the effects of IL-1 on chondrocyte, which is in accordance with results obtained in other cell types. Indeed, we showed that 15d-PGJ2 mainly, but also the drug troglitazone, that are ligands of PPAR␥ could significantly counteract the decrease in proteoglycan synthesis and NO production induced by IL-1. By contrast, PPAR␣ ligands such as Wy-14,643 or clofibrate had no effect on this process. Therefore, the presence of PPAR␥ in chondrocytes opens up new perspectives to modulate the effects of cytokines on cartilage by the use of specific ligands. The function of the two other transcription factors, PPAR␣ and ROR␣ identified in chondrocytes remains to be explored. Articular cartilage is a major component of the joint, and its mechanical properties depend on the integrity of the extracellular matrix, which is composed mainly of proteoglycans and collagens (1). Its progressive destruction, which results from an imbalance between the anabolic and catabolic processes, is a common feature of rheumatoid arthritis and osteoarthritis (OA).1 Interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) have been shown to inhibit the synthesis of cartilage components and to promote their degradation by activating metalloproteases (2, 3). Concurrently to these effects, they induce the production by chondrocytes of inflammatory mediators such as prostaglandins, nitric oxide (NO), and other reactive oxygen species (4). To date, most of the drugs marketed as nonsteroidal anti-inflammatory drugs or corticosteroids are unable to prevent cartilage damage (5). Thus, intense investigations are carried out to precise the transduction pathways that impair c...

SUMMARY We investigated the spatiotemporal distributions of the different peroxisome proliferator-activated receptor (PPAR) isotypes (α, β, and α) during development (Week 7 to Week 22 of gestation) of the human fetal digestive tract by immunohistochemistry using specific polyclonal antibodies. The PPAR subtypes, including PPARα, are expressed as early as 7 weeks of development in cell types of endodermal and mesodermal origin. The presence of PPARα was also found by Western blotting and nuclease-S1 protection assay, confirming that this subtype is not adipocyte-specific. PPARα, PPARβ, and PPARα exhibit different patterns of expression during morphogenesis of the digestive tract. Whatever the stage and the gut region (except the stomach) examined, PPARα is expressed at a high level, suggesting some fundamental role for this receptor in development and/or physiology of the human digestive tract.

Besides their involvement in the control of nuclear gene expression by activating several peroxisome proliferatoractivated receptors (PPARs), peroxisome proliferators influence mitochondrial activity. By analogy with the previous characterization of a mitochondrial T3 receptor (p43), we searched for the presence of a peroxisome proliferator target in the organelle. Using several antisera raised against different domains of PPARs, we demonstrated by Western blotting, immunoprecipitation and electron microscopy experiments, that a 45 kDa protein related to PPARQ Q2 (mt-PPAR) is located in the matrix of rat liver mitochondria. In addition, we found that the amounts of mt-PPAR are increased by clofibrate treatment. Moreover, in EMSA experiments mt-PPAR bound to a DR2 sequence located in the mitochondrial D-loop, by forming a complex with p43. Last, studies of tissue-specific expression indicated that mt-PPAR is detected in mitochondria of all tissues tested except the brain in amounts positively related to p43 abundance. ß

Abstract-Specific treatment of age-related aortic wall arteriosclerosis and stiffening is lacking. Because ligands for peroxisome proliferator-activated receptor ␥ have beneficial effects on the arterial wall in atherosclerosis, via an antiinflammatory mechanism, we investigated whether long-term pioglitazone (Pio) treatment protects against another form of vascular wall disease, arteriosclerosis. We evaluated, in a rat model of elastocalcinotic arteriosclerosis (hypervitaminosis D and nicotine [VDN]), whether Pio (3 mg ⅐ kg Ϫ1 per day for 1.5 month PO) attenuated arteriosclerosis and its consequences: aortic wall rigidity, increased aortic pulse pressure, and left ventricular hypertrophy. In VDN rats, medial calcification was associated with monocyte/macrophage infiltration and induction of tumor necrosis factor ␣ and interleukin 1␤. Pio increased nuclear peroxisome proliferator-activated receptor ␥ immunostaining in the aortic wall, decreased tumor necrosis factor ␣ (PϽ0.

Seasonal obesity and fasting-associated hibernation are the two major metabolic events governing hepatic lipid metabolism in hibernating mammals. In this process, however, the role of the nuclear receptor known as peroxisome proliferator-activated receptor (PPAR)-alpha has not been elucidated yet. Here we show, as in human, that jerboa (Jaculus orientalis) liver expresses both active wild-type PPARalpha (PPARalpha1wt) and truncated PPARalpha forms and that the PPARalpha1wt to truncated PPARalpha2 ratio, which indicates the availability of active PPARalpha1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPARalpha, during prehibernating and hibernating states, was demonstrated by the induction of its target genes, which encode peroxisomal proteins such as acyl-CoA oxidase 1, peroxisomal membrane protein 70, and catalase, accompanied by a concomitant induction of PPARalpha thermogenic coactivator PPARgamma coactivator-1alpha. Interestingly, sustained activation of PPARalpha by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPARalpha during prehibernation and overinduces its target genes, disrupting the prehibernation fattening process. In striking contrast, during fasting-associated hibernation, jerboas exhibit preferential up-regulation of hepatic peroxisomal fatty acid oxidation instead of the mitochondrial pathway, which is down-regulated. Taken together, our results strongly suggest that PPARalpha is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPARalpha and the activation of its target genes during hibernation bouts of jerboas.