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the insulin - like growth factor binding proteins ( igfbps ) are a superfamily comprised of six proteins ( igfbp-1 to 6 ) that bind to igfs with high affinity .
the existence of igfbps was discovered in the 1960s , and most studies were performed after the cloning of six igfbps in the early 1990s .
igfbps are not only involved in igf action , but also appear to regulate igf - independent functions including inhibition or activation of cell growth and induction of apoptosis .
igfbps interact with the acid - labile subunits and glycoproteins as well as insulin - like growth factors ( igfs ) in serum .
recently , another group of proteins which have a low affinity with igfs was discovered and named igfbp- related proteins ( igfbp - rps ) even though their structures are similar to the classical igfbps .
igfbps are regulated by proteases released from several tissues , and their igf binding affinity is negatively affected by proteolytic cleavage as well as phosphorylation of igfbps .
the characteristics of the six igfbps are summarized in table 1 . when igfs are secreted and circulate freely , they are unstable and easily degraded . to achieve functional stability , they need to bind igfbps for effective circulation in the blood . lately
, igfbps have demonstrated multiple functions as potential players in pathophysiological diseases including cancer , metabolic disease and neuronal disease . in this review ,
furthermore , we overview the transcriptional regulation of igfbp-1 and discuss current evidence that supports the effects of igfbp-1 gene expression on metabolic signaling .
understanding the transcriptional regulation of igfbps will expand our knowledge and research of the pathogenesis of metabolic disease and identify potential therapeutic targets against metabolic diseases .
igfbp-1 , among the igfbp family , is produced dominantly in the liver and kidney . the n- and
c - terminals of igbfp-1 are highly conserved among the igfbp isoforms and contribute to binding with igf .
igfbp-1 has central linker domains affected by post - translational modifications including proteolysis and phosphorylation .
igfbp-1 can affect igf-1 activity on cellular responses and independently activates igf-1 action on cell signaling .
igfbp-1 not only is an important determinant of igf activity , but also enhances glucose uptake in peripheral tissues and reduces glucose output in liver .
the phosphorylated form of igfbp-1 shows an enhanced affinity to igf-1 and ii , thereby reducing the utility of igfs .
regulation of igf activity by igfbps , however , is very complicated in both stimulatory and inhibitory mechanisms .
because the affinity of igf for igf receptor is limited by that of igfbp-1 to igfs , igfbp-1 inhibits free igf-1 levels and reduces igf signaling through the igf receptor .
this result indicates that high concentrations of igfbp-1 limit igf-1 bioavailability and activity of igf-1 with regard to metabolism .
igfbp-1 is also stimulated to very high concentrations during intensive exercise and in catabolic conditions , which is not completely explained by known regulators such as insulin and glucocorticoids .
the role of amp activated protein kinase ( ampk ) , an important signaling system for lipid and carbohydrate metabolism , in the regulation of igfbp-1 was studied in h4-ii - e rat hepatoma cells .
arsenic ( iii ) oxide and 5-aminoimidazole-4-carboxamide - riboside ( aicar ) were used as activators .
ampk was identified as a novel regulatory pathway for igfbp-1 by stimulating secretion and blocking the inhibitory effect of insulin .
the mammalian igfbp genes have been duplicated by chromosome copying since 1993 when locations of igfbp-1 and 2 genes were identified in the same regions as housekeeping gene clusters on human chromosomes 7 and 2 .
the evolutionary relationship between the different igfbp isoforms is well explained by genome duplication in vertebrates . along with the historical aspect for the analysis of igfbp evolution ,
igfbps form part of the growth - activating hormonal axis with igfs , which are released into the blood by the action of growth hormone .
igfbp-1 is located on the short arm of chromosome 7 and encoded by a 5.31 kb gene .
igfbp-1 has a molecular weight of about 25 kda and circulates in plasma as a heterodimer complex with igf-1 or ii .
igfbp-1 is present in the amniotic fluid at concentrations 100500 times higher than in plasma .
although igfbps are secreted into the blood and the physiological function of igfbps has been studied and is achieved via igf-1 and ii binding , this review focuses on igfbp gene expression regulated by transcription factors to help achieve metabolic homeostasis . from the point of view of igfbp gene expression
regulation of igfbp gene expression has been shown to be affected by hormones and growth factor - dependent molecular mechanisms , and it has been speculated that the dynamic regulations of igfbp gene expression may suggest the modulation of igf actions by systemic local effectors in various tissues . in this review ,
first , tamura et al . suggested that igfbp-1 gene expression was regulated by camp in human endometrial stromal cells ( escs ) .
camp is a commonly used decidualization stimulus , which is involved in the process of differentiating fibroblastoid stromal cells of the estrogen - primed endometrium by progesterone .
decidualization of stromal cells is induced by biochemical stimuli in vitro and in vivo camp is known to be an activator of igfbp-1 and increases igfbp-1 gene expression in escs .
two camp response elements ( cres ) have been found on the igfbp-1 promoter ( fig .
in addition to camp , the effect of metformin on decidualization was revealed in escs .
however , tamura et al . found a new function of metformin during decidualization processing through regulation of igfbp-1 .
the tamura group showed that igfbp-1 gene expression was reduced by metformin treatment , and il-8 and il-1 were stimulated after long - term exposure to metformin . even though the effect of metformin on igbfp-1 mrna expression was revealed ,
two progesterone response elements ( pres ) were identified ; in a long - term primary culture system , progesterone receptor ( pr ) directly activates igfbp-1 gene transcription by binding to pres ( fig .
2 ) . mutation of either the 5 or 3 half - site of the putative pre1 site ( from 193 to 179 bp ) reduced the promoter activity .
endogenous pr alone is insufficient to activate pre1 , indicating that the pre1 site of the igfbp-1 promoter mediates direct activation of pr upon transcription , specifically in decidualized stromal cells .
the primary physiological functions of igfbp-1 appear to be the suppression of igf action and a role in hypoglycemia .
moreover , igfbp-1 in liver may act as an igf - independent survival factor , resulting in pro - apoptotic signal reduction . recently , degenhardt et al .
found that igfbp-1 was produced by peroxisome proliferator - activated receptor ( ppar)- agonists independently of insulin .
the direct activator of gene expression by ppar ligands requires at least one binding site of ppar protein as a ppar response element ( ppre ) on the promoter of the ppar target gene .
a previous study has suggested that insulin inhibits hepatic igfbp-1 gene expression , and that igfbp-1 levels rapidly declined after feeding .
because igfbp-1 mrna expression increases during fasting , glucagon seems to stimulate plasma insulin level .
these results suggest that igfbp-1 gene transcription might play a key role in a complicated metabolic regulation .
moreover , igfbp-1 gene expression is also activated by glucocorticoids as well as hepatocyte nuclear factor ( hnf)-1 . suh and his colleague found a glucocorticoid response element ( gre ) located between 91 and 77 from the transcription start site of the rat igfbp-1 promoter .
also , three accessory regulatory sites for a hepatocyte nuclear factor-1 at 62/50 , an insulin response element at 108/99 , and an upstream site at 252/236 might be involved in dexamethasone - dependent activation .
specifically , suh et al . showed that hnf-1 and -1 transcription factors extracted from h4-ii - e cells could bind to the palindromic hnf-1 response element .
in addition , hnf-1 synergistically stimulates igfbp-1 gene expression with the glucocorticoid receptor bound to the gre , suggesting a possible mechanism for glucocorticoid - specific regulation .
in addition to the effect of glucocorticoid as a transcription factor of igfbp transcription through gre , igfbp-1 gene expression is regulated by caat / enhancer - binding proteins ( c / ebps )   ( fig .
the effects of insulin for gene expression are mediated through an insulin response element ( ire ) on the promoter of the target gene .
c / ebps are mainly expressed in the liver and adipose tissue where they play key roles in metabolism and cell differentiation .
they found that c / ebp protein forms a complex with other factors and inhibits insulin from binding to ire without interacting directly with the ire .
owing to inhibition of igfbp-1 expression by insulin , as mentioned above , this complex formation correlates with the capacity of insulin to control igfbp-1 promoter activity .
among the six igfbps , igfbp-1 represents the most important member with regard to insulin and glucose metabolism .
it is mainly produced in the liver and binds insulin - like growth factor-1 and ii .
hence , there is considerable evidence that dysregulation of igfbp-1 may contribute to metabolic disease . in this section ,
dysregulation of igfbp-1 as well as igfs in serum and cervical secretions induces metabolic disease and cardiovascular disease .
therefore , measurement of igfbp-1 level in various body fluids might be used in clinical diagnosis for such afflictions as insulin resistance , cardiovascular risk , hypoglycemia , and growth failure including fetal growth , pre - eclampsia , laron dwarfism , and ruptured fetal membranes .
on the other hand , serum igf-1 is reduced while igfbp-1 level is increased in type 1 diabetic patients .
. serum level of igfbp-1 is associated with metabolic nutritional factors and increases igf-1 concentration , resulting in reciprocal regulation of plasma insulin level .
various evidences suggest that malfunction of the igfbp-1 system is involved in the long - term complications of diabetes mellitus .
low levels of igfbp in serum identify insulin resistance as a marker of insulin sensitivity .
therefore , igfbp-1 level can correlate well with common indicators of insulin resistance in obese children and adults .
recent studies demonstrated that secretion of igfbp-1 is activated by proinflammatory cytokines like il-1 and tnf in hepg2 liver hepatocarcinoma cell lines .
in addition , il-6 upregulates mrna expression and secretion of igfbp-1 in a dose - dependent manner in hepatocytes which are co - cultured with liver macrophages .
therefore , the concentration of igfbp-1 regulated by cytokines may be involved in the initiation and progression of cardiovascular disease .
this article aimed to discuss the regulation of the igfbp-1 in metabolic diseases like diabetes and cardiovascular disease . in addition , a complex diagram for cis - elements of transcription factors on the igfbp-1 promoter have emerged suggesting that the molecular mechanism of their expression is dependent on transcription factors in cells and tissues .
although roles of igfbp-1 in the pathogenesis and progression of disease are complicated , the literature clearly indicates functional significance of igfbp-1 gene expression in vivo and in vitro .
therefore , the knowledge of igfbp-1 system regulation including its gene expression may offer a wide variety of interesting developments that are involved in the future strategy of igfbp - mediated therapy .
insulin - like growth factor binding proteins ( igfbps ) play a key role in insulin and insulin growth factor signaling and are known to be expressed in several tissues . 
 studies on the transcriptional regulation of igfbp genes in various cell types have suggested that igfbps control both systemic hormones and regulators . also , the complex regulatory mechanisms involved in both transcription and translation of igfbps provide evidence for molecular mechanisms by which growth factor- and hormone - mediated gene expression are regulated . in particular , igfbp-1 is known to be 
 an important regulator of igf activity and mainly regulates metabolism in mammals . in this review , 
 we focus on recent progress in elucidating the transcriptional regulation of igfbp-1 among igfbp isoforms .