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Mar 14, 2014 - are involved in cellular ROS metabolism [41]. Recent study suggested that STEAP1 is associated with the oxi- dative stress of Ewing tumor cells ...
Endocrine (2014) 47:372–379 DOI 10.1007/s12020-014-0230-1

REVIEW

STEAP4 and insulin resistance Xiaoling Chen • Zhiqing Huang • Bo Zhou • Huan Wang • Gang Jia • Guangmang Liu • Hua Zhao

Received: 18 November 2013 / Accepted: 26 February 2014 / Published online: 14 March 2014 Ó Springer Science+Business Media New York 2014

Abstract Obesity is a multifactorial disease that caused by the interactions between genetic susceptibility genes and environmental cues. Obesity is considered as a major risk factor of insulin resistance. STEAP4 is a novel antiobesity gene that is significantly down-regulated in adipose tissue of obese patients. Over-expression of STEAP4 can improve glucose uptake and mitochondrial function, and increase insulin sensitivity. STEAP4 expression is regulated by a variety of inflammatory cytokines, hormones, or adipokines. In this review, we discuss function of STEAP4 in regulating insulin resistance in adipose tissue in vivo, as well as in adipocytes in vitro. Keywords STEAP4  Insulin resistance  Glucose uptake  Mitochondrial function  Inflammation  Signal pathway

Introduction Obesity is an increasingly prevalent public health issue that is usually associated with insulin resistance (IR), type 2 diabetes, hypertension, and coronary heart disease

X. Chen  Z. Huang (&)  B. Zhou  H. Wang  G. Jia  G. Liu  H. Zhao Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, Sichuan, People’s Republic of China e-mail: [email protected]

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[1, 2]. At early onset of obesity, macrophages infiltrate into expanding adipose tissue and secrete proinflammatory cytokines, such as TNFa, IL-6, MCP-1, and IL-1b [3–6]. Therefore, identification of the genes defect in obesity would not only help to elucidate the underlying mechanisms of the obesity, but also be important for therapeutic treatment of obesity and its-associated pathogenesis. Six-transmembrane epithelial antigen of prostate 4 (STEAP4), also known as six-transmembrane protein of prostate 2 (STAMP2) or TNF-induced adipose-related protein (TIARP), belongs to the STEAP protein family and the metalloreductases family [7]. The STEAP4 counteracts the inflammation and insulin resistance in adipocytes and its expression level was significantly down-regulated in obese patients [8–10] and diabetic ApoE-/-/LDLR-/mice [11]. On contrary, recent studies reported that STEAP4 levels in both subcutaneous (sc) and visceral adipose tissue (VAT) were upregulated in obesity [12, 13]. The expression of STEAP4 was tightly controlled by inflammatory cytokines or adipokines, including TNFa, IL6, IL-1b, and leptin in adipocytes [14–16], and it was highly induced in human adipocytes differentiated in the presence of 1,25-dihydroxyvitamin D3 [17]. STEAP4 knockdown led to inhibition of adipogenesis by diminishing the expression of CCAAT/enhancer binding protein alpha (C/EBPa) and peroxisome proliferator-activated receptor gamma (PPARc) [18]. In addition, a previous study demonstrated that the STEAP4 gene expression was regulated by some insulin resistance-inducing hormones (GH, leptin, insulin, isoproterenol, dexamethasone) in 3T3L1 adipocytes [19]. Taken together, these data indicate that STEAP4 is critical involved in the development of insulin resistance. Here, we review the study of STEAP4 with a focus on its role in insulin sensitivity.

Endocrine (2014) 47:372–379

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459

1 Chr. 7q21

GXGXXA/G

NOR

TM1

TM2

TM3

FR

TM4

TM5

TM6

Fig. 1 Location of the STEAP4 gene on Chr7q21 and schematic illustration of its domain organization. Superscript numbers indicate the first and last amino acid, respectively. GXGXXA/G is the

Rossman fold motif; NOR NAPDH-oxidoreductase domain, FR ferric oxidoreductase domain; Boxes denote the transmembrane domains

The finding and structure of STEAP4

[9, 14, 23], and it was also detected in the endoplasmic reticulum (ER) [26].

The six-transmembrane epithelial antigen of the prostate (STEAP) was firstly discovered as a prostate-specific cellsurface antigen through suppression subtractive hybridizations. It was expressed predominantly in prostate and many other types of cancers [20]. Four STEAP proteins (STEAP1-4) were then identified, and their function was extensively studied [14, 21–24]. The full length STEAP4 mRNA (GenBank NM_024636) is 4,488 bp, with an open reading frame of 1380 bp, and 50 and 30 untranslated regions of 124 and 2,985 bp, respectively. The putative protein has 459 amino acids and is located at the chromosomal region 7q21.12 (Fig. 1). Among all STEAP proteins, cell-surface six transmembrane helical domain and intramembrane heme binding site are conserved [7, 14, 25]. STEAP4 also contains an oxidoreductase domain that lies on the cytosolic side of the membrane and serves as a transmembrane reductase [7]. In the N-termini, STEAP4 contains the Rossman fold motif (GXGXXA/G), a structure shared by proteins with oxidoreductase and dehydrogenase functions, with high affinity for nucleotides such as nicotinamide adenine dinucleotide (NAD) and flavin mononucleotide [7, 26]. The oxidoreductase domain of STEAP family shows 28 % identity to an archaeal protein F420H2: NADP? oxidoreductase (FNO) [7]. The FNO protein provides a better model for the cytosolic NADPH oxidoreductase domain of STEAP3 [27]. Analysis of the STEAP4 NADPH oxidase activity by crystallographic and kinetic characterization analysis confirmed its binding with NADPH with a conformation that is nearly identical to that of STEAP3 [25]. The FNO utilizes a 50 deazaflavin that is discovered in methanogenic archaea and some bacteria [28]. Accordingly, analysis of crystal structure of STEAP4 found it showed significant flavin dependent NADPH oxidase activities [25]. But loss of the C-terminal YedZ-like domain in the truncated STEAP4 oxidoreductase domain should lead to an aberrantly high, nonphysiological Km for flavin, which suggests that STEAP4 protein are indeed more closely related to the YedZ-like proteins than to ferric reductases and NADPHoxidoreductase (NOX) [29]. STEAP4 is predominantly found in the Golgi complex, trans-Golgi network, the plasma membrane and vesicular-tubular structures in the cytosol and colocalized with the early endosome antigen 1

The tissue distribution of STEAP4 Gene expression profiling is a method by which possible functions of genes can be hypothesized based on a very thorough and meticulous examination of their expression levels in different tissues. A large number of studies have shown that STEAP4 is expressed in a wide array of different tissues using gene expression profiling analysis [14, 21, 23, 30]. In human, STEAP4 is expressed in the prostate, placenta, heart, lung, fetal liver, adipose tissue, and bone marrow [9, 12, 23], and it is increased in prostate cancer and expressed to a lower extent in adult human liver [23]. In rodents, STEAP4 is expressed predominantly in white adipose tissue (WAT) [8, 14]. It is also expressed in brown adipose tissue, liver, heart, kidney, and skeletal muscle [14]. STEAP4 is expressed in differentiating 3T3-L1 adipocytes, and its expression increases with progression of differentiation [14]. This data suggest that STEAP4 gene may have multiple functions.

STEAP4 and glucose uptake There is considerable evidence suggesting that insulinstimulated glucose uptake is mediated primarily by glucose transporter, GLUT4 [31, 32]. GLUT4 was rapidly shuttled from a latent intracellular compartment to the plasma membrane upon insulin stimulation, resulting in increased glucose uptake in adipocytes [33]. Studies with different approach identified the roles of STEAP4 in insulin-stimulated glucose uptake [8, 11, 15, 34, 35]. Wellen et al. [8] showed that STAMP2-/- mice displayed impaired insulinstimulated glucose transport in adipocytes. Consistently, STEAP4 antibody inhibits while STEAP4 potentiates insulin’s effect on glucose uptake [15, 34]. Similarly, siRNA-mediated STEAP4 deficiency in mature human adipocytes significantly decreased insulin-stimulated glucose transport by decreasing GLUT4 translocation to the plasma membrane [35]. Furthermore, Qin et al. [36] found that monoclonal antibodies against STEAP4 were shown to decrease insulin-mediated GLUT4 translocation. In

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addition, STEAP4 over-expression significantly improved glucose tolerance in diabetic ApoE-/-/LDLR-/- mice [11]. These results suggest that the proper STEAP4 expression is important for maintaining glucose homeostasis, and STEAP4 could be an important player in insulin signaling.

STEAP4 and mitochondrial function Mitochondrial dysfunction is correlated with obesityassociated insulin resistance [37, 38]. The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS), which is known to impact insulin signaling [39]. STEAP proteins are homologues of NOX [40], which are involved in cellular ROS metabolism [41]. Recent study suggested that STEAP1 is associated with the oxidative stress of Ewing tumor cells [42]. Moreover, transcriptome and proteome analyses as well as functional studies reveal that STEAP1 expression is associated with elevated ROS levels [42]. These observations are in agreement with finding that STEAP1 over-expression promoted the thyroid epithelial cells growth through induction of the intracellular ROS level [43]. Qin et al. [36] evaluated the role of STEAP4 in mitochondria of adipocytes. Interestingly, they found that STEAP4 antibodies treatment affected mitochondria ultrastructure, reflected by condensed mitochondria with twisted and condensed cristae compared to those of control adipocytes, accompanied by increase of ROS levels and decrease of total ATP production and mitochondrial DW, indicating that STEAP4 may be involved in redox-regulation [36], similar in STEAP1. Iron is essential for cell proliferation, survival as well as mitochondrial function [44, 45]. Iron deficiency caused oxidative stress and enhanced production of ROS [46, 47]. Similar to other family members, STEAP2 and STEAP3, STEAP4 contains a C-terminal ferric oxidoreductase [48]. Thus, a role of STEAP4 in cellular iron homeostasis is suggested [7, 25, 26], through which it regulates the mitochondrial function. Alternative mechanisms that link STEAP4 with mitochondrial function should be further studied.

STEAP4 proteins in inflammation There is considerable evidence suggesting that the expression of STEAP4 in adipocytes was regulated by tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), IL1b, leptin, and nutritional stress [9–16, 30, 49, 50]. Knockout or knock-down of STEAP4 in adipocytes leads to inflammation-induced adipocyte dysfunction and insulin

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resistance [8, 10, 50]. VAT of STEAP4 knockout mice exhibits overt inflammation and impaired insulin signaling [8]. STEAP4 over-expression decreased pro-inflammatory cytokines (MCP-1, IL-6 and TNF-a) levels and increased anti-inflammatory cytokine levels (IL-10) in epididymal white adipose tissue and brown adipose tissues (BAT) [11]. Similarly, some other studies have shown that STEAP4 over-expression regulates insulin sensitivity of human adipocytes or HepG2 cells, and the inflammatory responses in macrophages [12, 15, 51, 52]. Recent study showed that the pro-inflammatory transcription factors C/EBPa and STAT3 can bind to the proximal promoter of STEAP4 and regulate its expression [49]. And C/EBPb directly controls the roles of STEAP4 in attenuating inflammation elicited by free fatty acids or LPS in hepatocytes [53]. In accordance, common variations in STEAP4 are associated with insulin resistance in Uygur Chinese general population [54–58] and Han Chinese population [59]. However, in French Caucasians and Norwegian common polymorphisms of STEAP4 gene were not associated with metabolic syndrome and obesity [60, 61], but showed more close interaction with insulin sensitivity [60]. STEAP4 is associated with TNFa-mediated inflammation in rheumatic and arthritis diseases [62–64]. A recent study demonstrated that TNFa treatment led to a significant induction of STEAP4 expression at both the mRNA and protein levels in human adipocytes [15]. In a cultured synovial fibroblast cell line, STEAP4 expression was augmented by TNFa activation [65]. This result was consistent with that the finding that STAMP4 is induced in a dosedependent manner by TNFa in mouse and human adipose tissue [9, 14]. In human peripheral blood of patients with rheumatoid arthritis, the expression of STEAP4 mRNA was significantly downregulated by TNFa antagonist such as infliximab [65]. IL-6 treatment significantly increased STEAP4 expression in human adipocytes [15]. This result is in line with data of Fasshauer et al. [30] who showed that the expression level of STEAP4 was up-regulated after IL-6 treatment in 3T3-L1 adipocyte. However, in human rheumatoid arthritis model, knock-down of STEAP4 by RNA interference enhanced the expression of IL-6 mRNA, while STEAP4 over-expression suppressed IL-6 expression [66]. Consistent with this finding, knockdown of STEAP4 by small interfering RNA resulted in augmented IL-6 secretion in the presence of either TNFa or high glucose challenges in 3T3-L1 adipocytes [8]. In line with these in vitro results, loss of STEAP4 expression in vivo efficiently induced inflammation in adipose tissue. Adipose tissue of STEAP4 knockout mice exhibited significantly elevated expression of inflammatory mediators such as TNFa, IL-6, MCP-1, SOCS-3, as well as hepatoglobin even on a standard rodent diet regime [8]. Leptin, an adipocyte-secreted hormone that regulate energy metabolism and insulin

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sensitivity, strongly inhibited STEAP4 expression at both mRNA and protein levels in human adipocytes [9, 12, 15]. Furthermore, STEAP4 expression is also induced by another proinflammatory cytokine, IL-1b, in human mesenchymal stem cell-derived adipocytes [16]. Recent data have in fact suggested that androgen [testosterone and dihydrotestosterone (DHT)] could prevent some metabolic syndrome such as abdominal obesity, insulin resistance, and prostate inflammation [67, 68], and the mRNA level of STEAP4 was significantly increased in androgen (testosterone and DHT)-treated VAT or LNCaP cells [23, 69], indicating that STEAP4 is an androgen-dependent gene required for insulin signaling. In addition, the STEAP4 expression is regulated by nutritional status in vitro. Serum fatty acids (such as oleic acid) markedly induced STEAP4 levels in adipocytes [8]. Recent evidence has indicated that adipose tissue, particularly in obesity subjects, can attract and lead to accumulation of macrophages [70], which would develop a low grade systematic inflammatory state, thereafter interferes insulin sensitivity in other peripheral tissue [71]. STEAP4 knockout mice exhibit increased numbers of macrophages in tissue, under basal conditions [51] and inflammation (macrophage infiltration of adipose tissue) [8]. STEAP4 over-expression significantly reduced macrophages infiltration in epididymal and BAT, accompanied by improved insulin sensitivity [11]. In addition, STEAP4 expression was positively correlated with CD206 gene expression [10], a marker of alternative anti-inflammatory macrophages (M2) in adipose tissue [72, 73]. Taken together, these findings indicate that STEAP4 may protect adipose tissue by recruiting anti-inflammatory factors, and that enhancing STEAP4 signaling could potentially be a target for human insulin resistance.

STEAP4 and iron and copper metabolism Iron is indispensable for many biochemical processes of life. Dysregulation of iron metabolism is associated with development insulin resistance [74–77]. Iron deficiency is frequently observed in obese individuals instead of nonobese ones [77]. Excessive absorption of iron leads to the production of ROS and its catalytic capacity to interfere with insulin secretion and may be involved in the development of insulin resistance [74–76]. Moreover, it has been shown that iron homeostasis disturbed by adipose tissue produces many pro-inflammatory cytokines (IL-1, IL-6, TNF-a) and adipokines (leptin, adiponectin, resistin) [78– 80]. There is a growing body of evidence indicating that iron homeostasis is also regulated by some hormones. Hepcidin, a recently identified peptide hormone, is a negative regulator of iron metabolism [81–83]. The hepcidin

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gene expression in the adipose tissue was positively correlated with inflammatory marker such as IL-6 and C-reactive protein in obesity [82–84]. Moreover, the hepatic hepcidin gene expression can be up-regulated by leptin [85, 86]. The increased hepcidin levels may lead to iron deficiency and result in obesity-associated insulin resistance. STEAP family members have been shown to possess both ferric reductase and cupric reductase activities [7, 87]. Extracellular iron transport is mainly mediated by the binding of diferric transferrin [88]. STEAP4 is specifically involved in the release of iron from transferrin and promotes the reduction of Fe3? to Fe2? [87]. The ferritin level was increased in obese patients, but the free iron concentration was negatively correlated with gene expression level of STEAP4 [13]. Knock-down of STEAP4 expression in vitro by lentivirus-mediated short hairpin RNAs decreased cellular ferrous iron, indicating that STEAP4 is a critical enzyme for cellular iron uptake [89]. The metabolism of iron and copper are intimately linked. The cellular copper availability can directly influence the uptake and metabolism of cellular iron. Cells acquire copper via copper transport protein (Ctr1), but only the reduced cuprous (Cu?) form is transportable [90]. The duodenal ferrireductase cytochrome b (Dcytb) may be involved in the reduction of dietary Cu2? [91]. Alternatively, STEAP proteins may also affect the absorption of intestinal copper. There is evidence that over-expression of STEAP4 could increase cupric reductase activity and resulted in increased uptake of copper in HEK293 cells [7]. Moreover, a recent report showed physiologically relevant Km values of STEAP4 for both Fe3? and Cu2? [26]. Duodenal cytochrome b (Dcytb) is a ferric/cupric reductase implicated in intestinal iron absorption. The reported Km values for Dcytb are 74 and 23 lM for iron and copper NTA chelates, respectively [92]. Gauss et al. [25] reported that the Km values for Fe3?-NTA and Cu2?-NTA were 4.8 ± 0.7 and 11.2 ± 4.4 lM, respectively, suggesting that STEAP4 has higher affinity than Dcytb for iron and copper and thus qualifying it as a physiologically relevant ferric and cupric reductase activity. Taken together, these results suggest that intestinal iron and copper absorption may be mediated by a STEAP4 protein. It will be interesting to directly investigate the role of STEAP4 in iron and copper metabolism and link it to obesity-associated insulin resistance.

Signal pathway of STEAP4 in the insulin resistance It is well known that insulin can activate the PI3K/Akt pathway, which is responsible for insulin-stimulated glucose uptake. In response to insulin, activation of

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Endocrine (2014) 47:372–379 Insulin receptor P

Nutrients (serum, free fatty acids)

P

Akt

Hormonal or inflammatory stimuli

STEAP4

GluT4 Glucose uptake

IL-6, MCP-1 SOCS-3

TNF-α Inflammation

(GH, TNF-α, IL1-β, IL-6, IL-8) Electron transport

Androgen (testosterone and DHT)

Mitochondrion function

ROS generation Oxidative stress responses other hormonal (Leptin, insulin, isoproterenol, dexamethasone)

STEAP4

Insulin sensitivity Fig. 2 Schematic illustration of STEAP4 physiologic functions. Nutritional stimuli (oleic acid or serum), inflammatory stimuli (TNF-a, IL1-b, IL-6 or IL-8), hormonal (GH, Insulin, isoproterenol, dexamethasone, leptin) induce expression of the STEAP4 in adipocytes. Expression of STEAP4 is required for normal insulin signaling, including tyrosine phosphorylation of both the insulin receptor (IR) and Akt kinase, induces GLUT4 translocation to the plasma membrane and stimulates the glucose uptake. Increase of STEAP4

expression leads to decreased production of inflammatory cytokines such as IL-6, MCP-1, and SOCS-3 by adipose tissue. And STEAP4 also decreased production of and ROS generation and increased electron transport. Androgen (testosterone and DHT) treatment increases the expression of STEAP4 mRNA. All these results would result in increased insulin sensitivity. Loss of STEAP4 expression also may lead to insulin resistance

phosphatidylinositol 3-kinase (PI3K) could lead to the phosphorylation of Akt [93]. Phosphorylated Akt could induce GLUT4 translocation to the plasma membrane, which directly increase glucose transport into cells [94]. Related studies showed that STEAP4 can affect insulinstimulated GLUT4 translocation and glucose transport by targeting the PI3K/Akt-signaling pathway in human adipocytes [35, 36]. Cheng et al. [35] found that RNAi-mediated STEAP4 deficiency significantly decreased GLUT4 translocation, glucose uptake, and the phosphorylation levels of PI3K (P85) and Akt. This finding was consistent with that of Qin et al. [36], who showed that the STEAP4 antibody induced a decrease in the insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate (IRS)-1, phosphorylation of PI3K (P85), and Akt. JNK is also an important mediator of insulin resistance and activation of JNK can decrease insulin activity [95]. In diabetic ApoE-/-/LDLR-/- mice, the phospho-JNK/JNK ratio was increase in WAT and BAT, but overexpression of STEAP4 could significantly decrease the ratio of phospho-JNK/JNK [11]. Taken together, these results revealed that STEAP4 gene is involved in the PI3K/Akt pathway and JNK signaling pathway. Further research is required to investigate whether other pathways are involved in STEAP4-mediated insulin resistance.

Conclusion and future directions

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Obesity is a multifactorial disease that results from the interactions between susceptibility genes and environmental factors and is considered as a major risk factor in insulin resistance. It is therefore critical in understanding the function of obesity-related genes in order to explore the pathology of the development of obesity and obesity-related complications. STEAP4 is a member of a family of metalloreductases that are involved in the reduction and transport of iron and copper and they are expressed in many tissues of human or rodents. STEAP4 is involved in diverse cellular processes including glucose metabolism, mitochondria electron transport, and inflammation response (Fig. 2). Overexpression of STEAP4 could improve insulin resistance via stimulating the glucose uptake and mitochondrial function, as well as via decreasing macrophages infiltration and the expression of pro-inflammatory cytokines. STEAP4 can affect insulin sensitivity via the PI3K/Akt-signaling pathway or JNKsignaling pathway. An important aspect in future research is its emerging role as a gene affecting human insulin resistance by in vivo animal model and up- or down-stream pathways involved in STEAP4-mediated insulin signaling. In addition, it will be necessary in future investigations to

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understand the mechanism and the role of STEAP4 ferric and cupric reductase activities in obesity associated insulin resistance and to explore the feasibility of STEAP4 as a new therapeutic target for obesity-associated insulin resistance.

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14.

15. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 31201811) and the Specific Research Supporting Program for Discipline Construction in Sichuan Agricultural University.

16.

The authors have declared that no competing

17.

Conflict of interest interests exist.

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