The Insulin-like Growth Factor-binding Protein 1 Gene Is a Primary Target of Peroxisome Proliferator-activated Receptors

Abstract

Insulin-like growth factor-binding protein 1 (IGFBP-1) is a biomarker for metabolic and hyperproliferative diseases. At the same time, the nuclear receptors peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the development of both the metabolic syndrome and various cancers. Here we demonstrate, in human hepatocellular carcinoma cells and in normal mouse liver, that IGFBP-1 mRNA expression is under the primary control of PPAR ligands. We applied an improved in silico screening approach for PPAR response elements (PPREs) and identified five candidate PPREs located within 10 kb of the transcription start site (TSS) of the IGFBP-1 gene. Chromatin immunoprecipitation assays showed that, in living cells, the genomic region containing the most proximal PPRE, at position ؊1200 (relative to the TSS), preferentially associates with multiple PPAR subtypes and various other components of the transcriptional apparatus, which include their heterodimerizing partner, retinoid X receptor, as well as phosphorylated RNA polymerase II, co-repressor, co-activator, and mediator proteins. Moreover, further chromatin immunoprecipitation assays demonstrated that the TSS regions of the IGFBP-1 gene and those of the related IGFBP-2, -5, and -6, but not of IGFBP-3 and -4 genes, bind PPARs as well. We also show that these additional PPAR binding genes contain a number of candidate PPREs and that their mRNA levels respond quickly to the presence of PPAR ligands, indicating that they are also primary PPAR target genes.Lipid level dysregulation is a characteristic common to some of the most prevalent medical disorders, including obesity, cardiovascular disease, and type 2 diabetes (1). Nuclear receptor transcription factors may have important roles to play in these diseases, because many of them have lipophilic compounds as ligands, including fatty acids and their metabolic derivatives (2), which appear to be important in either the normal functioning or a role in the disease process affecting the metabolic pathways. For example, native and oxidized polyunsaturated fatty acids as well as arachidonic acid derivatives, such as prostaglandins and prostacyclins, selectively bind the nuclear receptors peroxisome proliferator-activated receptors (PPARs) 3 ␣, ␥, and ␤/␦ and stimulate their transcriptional activity (3). PPARs are prominent players in the metabolic syndrome, because they are important regulators of lipid storage and catabolism (4). However, PPARs also regulate cellular growth and differentiation and therefore have as well an impact on hyperproliferative diseases, such as cancer (5). PPAR␥ is the best characterized member of the subfamily due to its prominent role in the regulation of differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells (6, 7). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of synthetic PPAR␥ ligands, such as the thiazolidinediones rosiglitazone, troglitazone, and piogl...

Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor γ in Human Skeletal Muscle Cells

“…5B). In our study, the binding activity of PPAR␥ was not changed by rosiglitazone, and similar phenomena have been reported by other researchers (10,19). EMSA with in vitro-translated PPAR␥ and RXR␣ showed that they specifically bound to hGPx3 (Ϫ2186) PPRE (data not shown).…”

Isolation stress for 30 days alters hepatic gene expression profiles, especially with reference to lipid metabolism in mice

“…On the other hand, the Igfbp1 gene was downregulated to the largest extent in the mouse liver after exposure to isolation stress for 30 days in the DNA microarray analysis. Recently, Igfbp1 was reported to be a primary target gene of peroxisome proliferator activated receptors (PPARs) (11). The present study found that the Ppara-mediated signal pathway was downregulated in the liver under the social stress (Fig.…”

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

“…We observed that emodin elevated IGFBP1 protein and mRNA expression, one of PPARγ target genes [24], in A549 and H1975 cells (Fig. 4A-B).…”

“…Data for the link of IGFBP1 and lung cancer risk are sparse, whether the expression and function of IGFBP1 in stimulating or inhibiting lung cancer growth and progression remain elusive. Of note, early study found that IGFBP1 gene was one of primary targets of PPARs [24]. …”