AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation

Hanlon, Paul; Ganem, Leonardo G.; Cho, Young C.; Yamamoto, Megumi; Jefcoate, Colin R.

doi:10.1016/s0041-008x(03)00083-8

Cited by 55 publications

(43 citation statements)

References 70 publications

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“…6) could indicates that AhR activation affects PPARα at transcriptional or post-transcriptional level by affecting the stability of PPARα mRNA. In fact, TCDD was reported to decrease the PPAR gamma mRNA expression in 10T1/2 cells through activation of ERK [15]. However, the mechanism of suppression of PPARα mRNA by AhR stimulation needs further investigation.…”

Section: Discussionmentioning

confidence: 98%

Down Regulation of Hepatic PPAR.ALPHA. Function by AhR Ligand

et al. 2004

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ABSTRACT. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) and related compounds. Peroxisome proliferator activated receptor alpha (PPARα) is a nuclear receptor involved in the maintenance of lipid and glucose homeostasis. In this study we hypothesized that one of the possible mechanisms for the effect of TCDD and its related chemicals on fat metabolism could be through down regulation of PPARα functions. We treated Wistar rats with an AhR ligand, Sudan III (S.III), and/or PPARα ligand, Clofibric Acid (CA), for 3 days. We analysed the expression of one of the PPARα-target gene products, CYP4A protein and its mRNA. We also tested HepG2 cells with the afore-mentioned treatments and evaluated their effects on PPAR α and RXRα protein. Treatment of Wistar rats with S.III was found to down regulates CYP4A protein expression and reduced its induction with CA. It also decreased mRNA expressions of CYP4A1, CYP4A2, CYP4A3 and PPARα. In HepG2 cells, PPARα and RXRα protein expression was decreased by S.III treatment in a dose dependent manner. Our results suggest that AhR has an inhibitory effect on PPAR α function and a new pathway by which AhR ligands could disturb lipid metabolism. KEY WORDS: AhR, CYP4A, PPARα rat, RXRα.J. Vet. Med. Sci. 66(11): 1377-1386, 2004 Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor deeply involved in the maintenance of lipid and glucose homeostasis [39] and is mainly expressed in liver, muscle and heart [3,40]. Activation of PPARα in liver, muscle and heart increases the expression and activity of lipoprotein lipase (LPL), an enzyme involved in lipolysis [35], and therefore increases the clearance of TG-rich lipoproteins, and circulating TG levels. PPARα agonist, fibrates, inhibits ApoCIII, which act as a natural inhibitor of LPL activity [5]. Treatment of diabetic db/db mice with a PPARα agonist normalizes circulating free fatty acids,TG, and glucose levels [2]. Moreover PPARα influences the expression of numerous genes implicated in major pathways of amino acid metabolism, and fasting PPARα-null mice have higher plasma urea concentration compared to wild type [19] PPARα agonists, fibrates, have been in use for over 40 years for the treatment of dyslipidemia, mainly due to their actions of lowering TG levels, raising HDL [9], and decreasing levels of LDL [40]. The CYP4A sub-family members which have a role in fatty acid and prostaglandin hydroxylation, are abundantly expressed in the liver and kidney [38]. The members of this sub-family are well known to be regulated by PPARα, which binds with RXRα to form heterodimers. These hetero-dimers then bind to enhancer elements PPRE on responsive genes including CYP4A family [17]. 20-hydroxyeicosatetraenoic acid is a major arachidonic acid metabolite of CYP4A isoforms in the microvasculature of the rat kidney and acts as a potent vasoconstrictor and mediator of the myogenic response [24]. Coll...

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Section: Discussionmentioning

confidence: 98%

Down Regulation of Hepatic PPAR.ALPHA. Function by AhR Ligand

et al. 2004

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“…The additional 30 amino acids at the N terminus of PPAR␥2 lead to an appreciably lower mobility on SDS polyacrylamide gels. Our previous studies have shown that in 10T1/2 cells, PPAR␥1 increases after approximately 12 h of stimulation and before PPAR␥2, which typically requires several days of insulin stimulation (Hanlon et al, 2003;Cho and Jefcoate, 2004). In Fig.…”

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confidence: 78%

“…Our previous studies have shown that TCDD synergizes with growth factors, including EGF and fibroblast growth factor in the suppression of PPAR␥1 expression (Hanlon et al, 2003). This synergy was proportional to the activation of Erk and completely dependent on this activity.…”

mentioning

confidence: 89%

2,3,7,8-Tetrachlorodibenzo-p-dioxin and Epidermal Growth Factor Cooperatively Suppress Peroxisome Proliferator-Activated Receptor-γ1 Stimulation and Restore Focal Adhesion Complexes during Adipogenesis: Selective Contributions of Src, Rho, and Erk Distinguish These Overlapping Processes in C3H10T1/2 Cells

Liu

Jefcoate²

2006

Molecular Pharmacology

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Stimulation of PPAR␥1 and adipogenesis in multipotential C3H10T1/2 cells by the combination of dexamethasone and 3-isobutyl-1-methylxanthine (DM) is suppressed by 2,3,7,8 tetrachlorodibenzodioxin (TCDD) (10 nM). This suppression requires sustained activation of extracellular signal-regulated kinase (Erk)1/2. We show that it arises from an effect of TCDD on epidermal growth factor (EGF) signaling. DM initiates an early loss of cell adhesion that is reversed by this TCDD/EGF synergy. Src kinase activity was completely essential for adhesion restoration, sustained Erk activation, and suppression of peroxisome proliferator-activated receptor (PPAR)␥1. MEK/Erk activity did not contribute, however, to TCDD-induced adhesion. Stimulation of adhesion may therefore precede elevation of Erk. Adhesion is produced by interaction of ␣␤ integrins with extracellular matrix proteins and subsequent Src-mediated phosphorylation of focal adhesion kinase (FAK, Tyr576/577) and paxillin (Tyr118). TCDD enhanced the steady state Src-mediated phosphorylation of FAK but not of paxillin. Protein tyrosine phosphatase (PTPase) inhibition by orthovanadate (OVA) showed that this Src activity is highly restricted by PTPases. Partial inhibition of PTPases by OVA mimicked TCDD in producing EGF-and Src-dependent effects on cell adhesion and PPAR␥1 suppression. TCDD may therefore induce a protein that enhances Src effectiveness at adhesion sites. Rho kinase (ROCK) inhibition blocked TCDD/EGF stimulation of clustered focal adhesion complexes without affecting either sustained Erk activation or suppression of PPAR␥1. Thus, this ROCKmediated clustering of integrin complexes is not needed for the effects of TCDD on Erk and PPAR␥1. A minimal cholesterol depletion with ␤-methylcyclodextrin attenuated TCDD effects on PPAR␥1 and Erk activation. TCDD intervention is therefore linked to extracellular proteins. It indicates that TCDD-enhanced stimulation of EGF signaling to Erk may derive from the initial ␣␤ integrin complexes.Extensive studies on adipocyte differentiation have used mouse embryonic fibroblastic cell models, including 3T3-L1 and 3T3-422A, which are already committed to the adipocyte lineage. C3H10T1/2 (10T1/2), a pluripotent progenitor cell type that is similar to mouse embryo fibroblasts, has also been used (Alexander et al., 1998). This cell type develops into fat, bone, or muscle cells according to the stimulus (Ntambi and Young-Cheul, 2000). In general, differentiation of 3T3-L1 and 10T1/2 cells is stimulated by a hormonal mixture (IDM) composed of insulin, dexamethasone (Dex), and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), which is administered to confluent cells along with serum renewal (Cowherd et al., 1999). Over approximately 48 h in 10T1/2 cells, IDM cooperatively directs several Article, publication date, and citation information can be found at

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“…In line with this possibility, recent studies have shown that there are cross-talks between the AhR system and the PPAR receptor system as well as with other nuclear receptor systems (discussed in ref. [51]). …”

Section: Effect Of Tcdd and Hf Diet On Animal Body And Organ Weightmentioning

confidence: 99%

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Zhu

Gallo

Burger

et al. 2008

Toxicology and Applied Pharmacology

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We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every two weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 μg/kg b.w. once every two weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD, a potent Ah receptor agonist, may have an obesity-inducing effect in animals fed a HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals a HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2-and 4-hydroxylation of 17β-estradiol in animals fed a control diet, but surprisingly not in animals fed a HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of 1 This study was supported, in part, by a grant from the American Cancer Society (RSG-02-143-01-CNE to BTZ) and also by grants from the NIH (CA92391, CA97109 and ES05022). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD. NIH Public Access

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AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation

Cited by 55 publications

References 70 publications

Down Regulation of Hepatic PPAR.ALPHA. Function by AhR Ligand

Down Regulation of Hepatic PPAR.ALPHA. Function by AhR Ligand

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

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