Transcriptional Suppression of the Transferrin Gene by Hypolipidemic Peroxisome Proliferators

Hertz, Rachel; Seckbach, Mesha; Zakin, Mario M.; Bar‐Tana, Jacob

doi:10.1074/jbc.271.1.218

Cited by 76 publications

(51 citation statements)

References 40 publications

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“…This response element binds HNF-4, a constitutively active orphan nuclear receptor whose DNA-binding specificity overlaps that of PPAR-RXR heterodimers. Other investigators have shown that PPAR␣ antagonizes HNF-4 by downregulating its expression in liver and by binding nonproductively to HNF-4 response elements (47). These observations, along with our demonstration that PUFAs promote the binding of PPAR␣/␦-RXR␣ heterodimers, suggest that PUFAs may suppress transcription by displacing constitutively active HNF-4 and replacing it with an abortive PPAR␣/␦-RXR␣ complex.…”

Section: Discussionsupporting

confidence: 59%

Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ

Forman

Chen

Evans

1997

Proc. Natl. Acad. Sci. U.S.A.

1,965

1,421

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Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor ␣ (PPAR␣) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPAR␣/␦ and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPAR␣ or PPAR␦. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders.

show abstract

Section: Discussionsupporting

confidence: 59%

Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ

Forman

Chen

Evans

1997

Proc. Natl. Acad. Sci. U.S.A.

1,965

1,421

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“…DR1 elements are quite promiscuous, thus allowing binding of other transcription factors, including HNF4␣, PPAR␣/RXR␣, RXR␣ homodimers, retinoic acid receptor ␣/RXR␣ heterodimers, and chicken ovalbumin upstream promoter transcription factor I and II (Nakshatri and Bhat-Nakshatri, 1998), suggesting that these factors potentially could compete for binding to specific DR1 elements. Competitive binding of HNF4␣ and PPAR␣/RXR␣ to DR1 elements as a mechanism for modulating transcriptional activation of target genes has been proposed (Hertz et al, 1995(Hertz et al, , 1996Marrapodi and Chiang, 2000). For example, HNF4␣ was reported to bind to the ACOX-PPRE (Sladek, 1994), and in HepG2 cells, the apoC-III promoter activity was affected by hypolipidemic drugs (Hertz et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Mouse Hepatic α-Amino-β-Carboxymuconate-ϵ-Semialdehyde Decarboxylase, a Key Enzyme in the Tryptophan-Nicotinamide Adenine Dinucleotide Pathway, by Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptor α

Shin¹,

Kim²,

Inoue³

et al. 2006

Mol Pharmacol

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Nicotinamide adenine dinucleotide (NAD) plays a critical role in the maintenance of cellular energy homeostasis. ␣-Amino-␤-carboxymuconate--semialdehyde decarboxylase (ACMSD) is the key enzyme regulating de novo synthesis of NAD from L-tryptophan (Trp), designated the Trp-NAD pathway. Acmsd gene expression was found to be under the control of both hepatocyte nuclear factor 4␣ (HNF4␣) and peroxisome proliferator-activated receptor ␣ (PPAR␣). Constitutive expression of ACMSD mRNA levels were governed by HNF4␣ and downregulated by activation of PPAR␣ by the ligand Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid]), as revealed by studies with hepatic HNF4␣-null mice and PPAR␣-null mice, respectively. Transient transfection and electrophoretic mobility shift analyses showed an HNF4␣ binding site in the Acmsd gene promoter that directed transactivation of reporter gene constructs by HNF4␣. The Acmsd promoter was not responsive to PPAR␣ in transactivation assays. Wy-14,643 treatment decreased HNF4␣ protein levels in wild-type, but not PPAR␣-null, mouse livers, with no changes in HNF4␣ mRNA. These results show that Wy-14,643, through PPAR␣, posttranscriptionally down-regulates HNF4␣ protein levels, leading to reduced expression of the HNF4␣ target gene Acmsd.

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“…The widespread effects of PPC exposure on hepatocyte gene regulation indicate that down-regulation could result from PPAR␣-dependent interference in liver-specific transcription factors that control the liver phenotype. Activated PPAR has been shown to disrupt and down-regulate HNF-4-mediated regulation of apolipoprotein cIII (Hertz et al, 1995) and transferrin (Hertz et al, 1996) genes by interfering with the ability of HNF-4 to activate at a PPRE-like element in the promoter regions of these genes as well as the HNF-4 gene itself. Although the down-regulation of HNF-4 expression or activity by PPAR may be important for expression of some liverspecific genes, the ability of HNF-4 to positively regulate expression of P450 2C family members does not correlate with their down-regulation by PPC.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

et al. 1998

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In this study, we show that peroxisome proliferator chemical (PPC) exposure leads to alterations in the expression of genes in rat liver regulated by the sex-specific growth hormone secretory pattern and induced during inflammation. Expression of the male-specific cytochrome P450 (P450) 2C11 and ␣2 urinary globulin (␣2u) genes and the female-specific P450 2C12 gene was down-regulated by some PPC. Expression of P450 2C13, also under control by the sex-specific growth hormone secretory pattern, was not altered by PPC treatment, indicating that regulation of CYP2C family members does not involve perturbation of the growth hormone secretory pattern. In contrast to the increases in expression observed when inflammation was induced in male rats, two positive acute-phase response genes, ␣ 1 -acid glycoprotein and ␤-fibrinogen, were decreased by PPC exposure. The down-regulation of the P450 2C11 by WY-14,643 could be reproduced in cultured rat hepatocytes, indicating the down-regulation is a direct effect. Experiments in wild-type mice and mice that lacked a functional peroxisome proliferator-activated receptor-␣ gene showed that down-regulation by WY of ␣ 1 -acid glycoprotein, ␤-fibrinogen, and a mouse homologue of ␣2u was dependent on peroxisome proliferator-activated receptor-␣ expression. Our results demonstrate that PPC exposure leads to down-regulation of diverse liver-specific genes, including CYP2C family members important in hormonal homeostasis and acute-phase response genes important in inflammatory responses.

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Transcriptional Suppression of the Transferrin Gene by Hypolipidemic Peroxisome Proliferators

Cited by 76 publications

References 40 publications

Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ

Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ

Regulation of Mouse Hepatic α-Amino-β-Carboxymuconate-ϵ-Semialdehyde Decarboxylase, a Key Enzyme in the Tryptophan-Nicotinamide Adenine Dinucleotide Pathway, by Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptor α

Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

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