Stabilization of Peroxisome Proliferator-Activated Receptor α by the Ligand

Hirotani, Masaki; Tsukamoto, Tomoko; Bourdeaux, Jessie; Sadano, Hiroyuki; Osumi, Takashi

doi:10.1006/bbrc.2001.5739

Cited by 28 publications

(25 citation statements)

References 27 publications

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“…In this report, it is shown that the ubiquitin-proteasome pathway controls the degradation of PPAR␣ protein and as such modulates the concentration of PPAR␣ in hepatocytes. Results from pulse-chase experiments demonstrate that PPAR␣ protein has a short half-life, which is extended by liganding of the receptor, results that confirm and extend data that appeared when this work was in progress (27). In addition, we show that PPAR␣ protein stabilization by its ligand is associated with a reduction in ubiquitination of PPAR␣ protein.…”

Section: Discussionsupporting

confidence: 86%

Peroxisome Proliferator-activated Receptor α (PPARα) Turnover by the Ubiquitin-Proteasome System Controls the Ligand-induced Expression Level of Its Target Genes

Blanquart¹,

Barbier²,

Fruchart

et al. 2002

Journal of Biological Chemistry

127

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Peroxisome proliferator activated-receptor ␣ (PPAR␣) is a ligand-activated transcription factor belonging to the nuclear receptor family. PPAR␣ is implicated in the regulation of lipid and glucose metabolism and in the control of inflammatory response. Recently, it has been demonstrated that a number of nuclear receptors are degraded by the ubiquitin-proteasome pathway. Since PPAR␣ exhibits a circadian expression rhythm and since PPAR␣ is rapidly regulated under certain pathophysiological conditions such as the acute phase inflammatory response, we hypothesized that PPAR␣ protein levels must be under tight control. Here, we studied the mechanisms controlling PPAR␣ protein levels and their consequences on the transcriptional control of PPAR␣ target genes. Using pulse-chase experiments, it is shown that PPAR␣ is a short-lived protein and that addition of its ligands stabilizes this nuclear receptor. By transient cotransfection experiments using expression vectors for PPAR␣ and hemagglutinin-tagged ubiquitin, it is demonstrated that PPAR␣ protein is ubiquitinated and that its ligands decrease the ubiquitination of this nuclear receptor, thus providing a mechanism for the ligand-dependent stabilization observed in pulse-chase experiments. In addition, treatment with MG132, a selective proteasome inhibitor, increases the level of ubiquitinated PPAR␣ and inhibits its degradation in transfected cells. Furthermore, MG132 treatment enhances the level of endogenous PPAR␣ in HepG2 cells. Finally, transient transfection and quantitative reverse transcription-PCR show that inhibition of PPAR␣ degradation increases its transcriptional activation and expression of target genes such as apoA-II and fatty acid transport protein (FATP). Taken together, these data demonstrate that PPAR␣ is degraded by the ubiquitin-proteasome system in a ligand-dependent manner. Regulation of its degradation provides a novel regulatory mechanism of transcriptional activity of this nuclear receptor.The peroxisome proliferator-activated receptors (PPARs) 1 are members of the nuclear receptor superfamily that act as ligand-dependent transcription factors. PPAR␣ is highly expressed in liver, skeletal and cardiac muscle, and proximal tubular epithelium of kidney. A significant expression of PPAR␣ has also been shown in endothelial cells, smooth muscle cells, and cells involved in the inflammatory process (1). The ligands of PPAR␣ are natural fatty acids and derivatives such as leukotriene B4 and 8-S-hydroxyeicosatetraenoic acid or oxidized phospholipids from oxidized low density lipoprotein. The fibrates hypolipidemic drugs are synthetic PPAR␣ ligands (1). PPAR␣ plays a role in intracellular fatty acid metabolism and in triglyceride metabolism by regulating genes involved in the transport and degradation of fatty acids in mitochondria and peroxisomes (2). PPAR␣ is also implicated in the metabolism of lipids and lipoproteins. As a result, PPAR␣ activation decreases the hepatic very low density lipoprotein secretion and plasma triglyceride levels (3). Fur...

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Section: Discussionsupporting

confidence: 86%

Peroxisome Proliferator-activated Receptor α (PPARα) Turnover by the Ubiquitin-Proteasome System Controls the Ligand-induced Expression Level of Its Target Genes

Blanquart¹,

Barbier²,

Fruchart

et al. 2002

Journal of Biological Chemistry

127

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“…Only vitamin D3 receptor has been previously shown to be stabilized by the ligand with similar kinetics (41). PPAR␥ was degraded rather rapidly upon exposure to ligands (42), whereas PPAR␣ was stabilized in the presence of ligands but only transiently (43,44). An increase of PPAR␣ protein level was seen within 3 h and was followed by rapid proteolysis upon continuous exposure to ligands (43).…”

Section: Discussionmentioning

confidence: 92%

Block of Nuclear Receptor Ubiquitination

Genini

Catapano

2007

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor ␦ (PPAR␦) is a ligand-activated transcription factor involved in many physiological and pathological processes. PPAR␦ is a promising therapeutic target for metabolic, chronic inflammatory, and neurodegenerative disorders. However, limited information is available about the mechanisms that control the activity of this nuclear receptor. Here, we examined the role of the ubiquitinproteasome system in PPAR␦ turnover. The receptor was ubiquitinated and subject to rapid degradation by the 26 S proteasome. Unlike most nuclear receptors that are degraded upon ligand binding, PPAR␦ ligands inhibited the ubiquitination of the receptor, thereby preventing its degradation. Ligand binding was required for inhibition of the ubiquitination since disruption of the ligand binding domain abolished the effect. Sitedirected mutagenesis showed that the DNA binding domain was also required, indicating that ligands preferentially stabilized the DNA-bound receptor. In contrast, the activation function-2 domain and co-repressor binding site were not involved in ligand-induced stabilization. Block of ubiquitination by ligands may be an essential step to avoid rapid degradation of a receptor, like PPAR␦, with a very short half-life and sustain its transcriptional activity once it is engaged in transcriptional activation complexes.Peroxisome proliferator-activated receptors (PPARs) 2 belong to the superfamily of nuclear hormone receptors and act as ligand-activated transcription factors (1). PPARs are activated by a diverse group of lipophilic compounds, including long-chain fatty acids, prostaglandins, and leukotrienes (2). PPARs form heterodimers with the retinoic X receptor and bind DNA in correspondence to specific PPAR response elements (PPRE) located in the promoter of target genes (1). Unliganded receptors maintain the promoter in a repressive or inactive state (3). Ligand binding induces a conformational remodeling of the receptor, resulting in the release of co-repressor molecules and recruitment of co-activators necessary for transcriptional activation (3). The PPAR subfamily includes three isotypes, named ␣, ␦ (or ␤), and ␥, that share extensive structural homology (1). Although all three isotypes act as lipid sensors and are involved in various aspects of lipid metabolism, they have distinct tissue distribution, ligand specificity, and functions (2, 4). PPAR␣ is involved in fatty acid metabolism, and high affinity ligands of this receptor, like fenofibrate and bezafibrate, are effective hypolipidemic drugs (5). PPAR␥ prevalently controls lipid and glucose metabolism, and PPAR␥ agonists, like rosiglitazone and pioglitazone, are widely used antidiabetic drugs (6). PPAR␦, which is the less studied of the three isotypes, has been implicated in wound healing, inflammatory responses, and embryo implantation in addition to lipid metabolism (4, 7). PPAR␦ is a potential therapeutic target for diseases such as atherosclerosis and other inflammatory, metabolic, and neurodegenerative disorders (7)...

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“…Despite similar enhancement in the gene expression of both PPAR and PPAR , E 2 resulted in a selective up-regulation of the protein abundance of PPAR alone. Recent data suggests that PPAR ligand binding, which initiates dimerization with the nuclear binding partner retinoid X receptor (RXR), minimizes protein degradation by stabilizing the PPAR protein (Hirotani et al 2001). It is tempting to speculate that in skeletal muscle E 2 may generate a PPAR specific ligand, in contrast to the previous evidence for a PPAR ligand in the mallard duck uropygial gland (Ma et al 1998).…”

Section: Discussionmentioning

confidence: 97%

17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle

Campbell

Mehan

Tunstall

et al. 2003

Journal of Molecular Endocrinology

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This study examined the actions of 17β-estradiol (E 2 ) and progesterone on the regulation of the peroxisome proliferator-activated receptors (PPARα and PPARγ) family of nuclear transcription factors and the mRNA abundance of key enzymes involved in fat oxidation, in skeletal muscle. Specifically, carnitine palmitoyltransferase I (CPT I), β-3-hydroxyacyl CoA dehydrogenase (β-HAD), and pyruvate dehydrogenase kinase 4 (PDK4) were examined. Sprague-Dawley rats were ovariectomized and treated with placebo (Ovx), E 2 , progesterone, or both hormones in combination (E+P). Additionally, sham-operated rats were treated with placebo (Sham) to serve as controls. Hormone (or vehicle only) delivery was via time release pellets inserted at the time of surgery, 15 days prior to analysis. E 2 treatment increased PPARα mRNA expression and protein content (P<0·05), compared with Ovx treatment. E 2 also resulted in upregulated mRNA of CPT I and PDK4 (P<0·05). PPARγ mRNA expression was also increased (P<0·05) by E 2 treatment, although protein content remained unaltered. These data demonstrate the novel regulation of E 2 on PPARα and genes encoding key proteins that are pivotal in regulating skeletal muscle lipid oxidative flux.

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Stabilization of Peroxisome Proliferator-Activated Receptor α by the Ligand

Cited by 28 publications

References 27 publications

Peroxisome Proliferator-activated Receptor α (PPARα) Turnover by the Ubiquitin-Proteasome System Controls the Ligand-induced Expression Level of Its Target Genes

Peroxisome Proliferator-activated Receptor α (PPARα) Turnover by the Ubiquitin-Proteasome System Controls the Ligand-induced Expression Level of Its Target Genes

Block of Nuclear Receptor Ubiquitination

17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle

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