Expression and clinical significance of obesity-associated gene STEAP4 in obese children

Xu, Huimin; Cui, Yaohui; Wang, W G; Cheng, Hong; Sun, Yajun; Zhao, Hong; Yan, Yongqiang

doi:10.4238/gmr.15048705

Cited by 10 publications

(9 citation statements)

References 21 publications

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“…2011; Kim et al. 2015; Ozmen et al 2016; Xu et al 2016). Additionally, STEAP4 expression in both fat and muscle was reduced among the most insulin resistant individuals independent of BMI (Elbein et al.…”

Section: Regulatory Influences On Steap4 Expressionmentioning

confidence: 99%

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

Scarl

Lawrence

Gordon

et al. 2017

Journal of Endocrinology

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Preserving energy homeostasis in the presence of stressors such as proinflammatory cytokines and nutrient overload is crucial to maintaining normal cellular function. Six-transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase involved in iron and copper homeostasis, is thought to play a potentially important role in the cellular response to inflammatory stress. Genome-wide association studies have linked various mutations in STEAP4 with the development of metabolic disorders such as obesity, metabolic syndrome, and type 2 diabetes. Several studies have shown that expression of Steap4 is modulated by inflammatory cytokines, hormones, and other indicators of cellular stress, and that STEAP4 may protect cells from damage, helping to maintain normal metabolic function. STEAP4 appears to be particularly relevant in metabolically oriented cells, such as adipocytes, hepatocytes, and pancreatic islet cells. These cells struggle to maintain their function in iron or copper overloaded states, presumably due to increased oxidative stress, suggesting STEAP4’s role in metal homeostasisis critical to the maintenance of cellular homeostasis in general, and in preventing the onset of metabolic disease. In this review, we explore genetic associations of STEAP4 with metabolic disorders, and we examine STEAP4 tissue expression, subcellular localization, regulation, structure, and function as it relates to metabolic diseases. We then examine how STEAP4’s role as a regulator of cellular iron and copper may relate to type 2 diabetes.

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Section: Regulatory Influences On Steap4 Expressionmentioning

confidence: 99%

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

Scarl

Lawrence

Gordon

et al. 2017

Journal of Endocrinology

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“…SNP rs408118325 on chromosome 4 maps near the STEAP4 metalloreductase gene (STEAP4, also known as STAMP2), a member of the TNF-a inducible proteinencoding family. STEAP4 encodes a metalloreductase abundantly expressed in human adipose tissue and involved in adipocyte development and metabolism, insulin sensitivity, and inflammation (Ohgami et al 2006;Zhang et al 2008;Catalan et al 2013;Ozmen et al 2016;Xu et al 2016). The two SNPs on chromosome 6, rs402128848 and rs401248376, are located in a region downstream of the C-terminal binding protein 1 gene (CTBP1).…”

Section: Gene Annotationmentioning

confidence: 99%

Genome‐wide association analysis identifies the genetic basis of fat deposition in the tails of sheep (Ovis aries)

Ren

Yang

et al. 2017

Animal Genetics

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SummaryFat-tailed sheep (Ovis aries) can survive in harsh environments and satisfy human's intake of dietary fat. However, the animals require more feed, which increases the cost of farming. Thus, most farmers currently prefer thin-tailed, short-tailed or docked sheep. To date, the molecular mechanism of the formation of fat tails in sheep has not been completely elucidated. Here, we conducted a genome-wide association study using phenotypes and genotypes (the Ovine Infinium HD SNP BeadChip genotype data) of two breeds of contrasting tail types (78 Small-tailed and 78 Large-tailed Han sheep breeds) to identify functional genes and variants associated with fat deposition. We identified four significantly (rs416433540, rs409848439, rs408118325 and rs402128848) and three approximately associated autosomal SNPs (rs401248376, rs402445895 and rs416201901). Gene annotation indicated that the surrounding genes (CREB1, STEAP4, CTBP1 and RIP140, also known as NRIP1) function in lipid storage or fat cell regulation. Furthermore, through an X-chromosome-wide association analysis, we detected significantly associated SNPs in the OARX: 88-89 Mb region, which could be a strong candidate genomic region for fat deposition in tails of sheep. Our results represent a new genomic resource for sheep genetics and breeding. In addition, the findings provide novel insights into genetic mechanisms of fat deposition in the tail of sheep and other mammals.

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“…Known and putative upregulating factors include pro-inflammatory cytokines [7,13,32,33], nutrient intake [21], and acute cellular stress [13,21]. Downregulating factors of STEAP4 include obesity [25–28], HbA1c/diabetic condition [26], and chronic inflammation. We discuss below how these putative competing regulatory factors may impact islet STEAP4 expression.…”

Section: Discussionmentioning

confidence: 99%

“…A pair of studies showed that STEAP4 levels in adipocytes and white adipose tissue were increased in obesity [23,24], whereas other studies showed that STEAP4 was downregulated in obese people [25–28]. In yet another study, STEAP4 gene expression in both fat and muscle was reduced among the most insulin resistant individuals independent of BMI [34].…”

Section: Discussionmentioning

confidence: 99%

“…Human abdominal subcutaneous and omental white adipose tissue collected from insulin-resistant individuals was associated with increased STEAP4 levels in a pair of studies [23,24]. By contrast, several similar studies have demonstrated decreased STEAP4 expression in visceral adipose tissue with increased adiposity or body mass index (BMI) [25–28]. …”

Section: Introductionmentioning

confidence: 99%

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STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation

et al. 2017

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Six-transmembrane epithelial antigen of the prostate 4 (STEAP4) is a metalloreductase that has been shown previously to protect cells from inflammatory damage. Genetic variants in STEAP4 have been associated with numerous metabolic disorders related to obesity, including putative defects in the acute insulin response to glucose in type 2 diabetes (T2D). Purpose We examined whether obesity and/or T2D altered STEAP4 expression in human pancreatic islets. Methods Human islets were isolated from deceased donors at two medical centers and processed for quantitative PCR. Organ donors were selected by status as non-diabetic or having T2D. Site1 (Edmonton): N=13 T2D donors (7M, 6F), N=20 non-diabetic donors (7M, 13F). Site2 (Virginia): N=6 T2D donors (6F), N=6 non-diabetic donors (3M, 3F). Results STEAP4 showed reduced islet expression with increasing BMI among all donors (P<0.10) and non-diabetic donors (P<0.05) from Site1; STEAP4 showed reduced islet expression among T2D donors with increasing HbA1c. Islet STEAP4 expression was also marginally higher in female donors (p<0.10). Among T2D donors from Site2, islet insulin expression was reduced, STEAP4 expression was increased, and white blood cell counts were increased compared to non-diabetic donors. Islets from non-diabetic donors that were exposed overnight to 5ng/ml IL-1β displayed increased STEAP4 expression, consistent with STEAP4 upregulation by inflammatory signaling. Conclusions These findings suggest that increased STEAP4 mRNA expression is associated with inflammatory stimuli, whereas lower STEAP4 expression is associated with obesity in human islets. Given its known protective role, downregulation of STEAP4 by chronic obesity suggests a mechanism for reduced islet protection against cellular damage.

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Expression and clinical significance of obesity-associated gene STEAP4 in obese children

Cited by 10 publications

References 21 publications

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

Genome‐wide association analysis identifies the genetic basis of fat deposition in the tails of sheep (Ovis aries)

STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation

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