Stamp2 Controls Macrophage Inflammation through Nicotinamide Adenine Dinucleotide Phosphate Homeostasis and Protects against Atherosclerosis

Freyhaus, Henrik ten; Calay, Ediz S.; Yalçin, Ali; Vallerie, Sara N.; Yang, Ling; Calay, Zerrin; Saatcioglu, Fahri; Hotamışlıgil, Gökhan S.

doi:10.1016/j.cmet.2012.05.009

Cited by 39 publications

(52 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…STEAP4 overexpression reduced rates of atherosclerosis and plaque formation in diabetic mice (Wang et al 2014), while its deficiency promoted atherosclerosis (Freyhaus et al 2012). Similarly, STEAP4 overexpression reduced migration of neutrophil-like HL60 (Tanaka et al 2012a) and reduced IL-6 and IL-8 cytokine expression (Tanaka et al 2012b), whereas siRNA knockdown of STEAP4 increased cytokine signaling in patients with rheumatoid arthritis (Tanaka et al 2012b), again consistent with a role for Steap4 in a negative feedback loop.…”

Section: Regulatory and Protective Influences Of Steap4mentioning

confidence: 99%

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

Scarl

Lawrence

Gordon

et al. 2017

Journal of Endocrinology

View full text Add to dashboard Cite

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.

show abstract

Section: Regulatory and Protective Influences Of Steap4mentioning

confidence: 99%

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

Scarl

Lawrence

Gordon

et al. 2017

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…In addition to its cell surface metalloreductase activity, it has also been suggested to facilitate trafficking in endocytic and exocytic pathways and to play a role in macrophage inflammation, where it protects against atherosclerosis (6,12). In addition, the literature also frequently identifies Steap4 as an obesity-related protein associated with insulin sensitivity, with knockdown or loss of Steap4 leading to insulin resistance (6,(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

The Crystal Structure of Six-transmembrane Epithelial Antigen of the Prostate 4 (Steap4), a Ferri/Cuprireductase, Suggests a Novel Interdomain Flavin-binding Site

Gauss

Kleven

Sendamarai

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:In-depth biochemical and structural analyses of Steap4 are lacking. Results: Crystallographic and kinetic characterization of Steap4 metalloreductase and flavin-dependent NADPH oxidase activities are reported. Conclusion: Physiologically relevant ferric/cupric reductase and flavin-dependent NADPH oxidase activities are observed at neutral and endosomal pH; the N-terminal tail is dispensable for these activities. Significance: Metalloreductase activity should be considered in Steap4-associated insulin resistance.

show abstract

“…Several studies suggest that STEAP4 plays a protective role in the face of inflammatory stress in models of metabolic disorders [9,21,22,41,42]. Thus, if obesity results in reduced STEAP4 expression levels, this may depress a normal compensatory responses to cellular stress.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond its known role as a metalloreductase [14], studies have shown that STEAP4 plays an anti-inflammatory or protective role from cellular damage in adipocytes [15,9], mesangial cells [16], hepatocytes [17–19], and synoviocytes [20]. In studies of mice, the STEAP4-/- phenotype includes the spontaneous development of obesity, insulin resistance, and eventual hyperglycemia [21], as well as signs of atherosclerosis [22], also suggesting a protective role for the protein.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Stamp2 Controls Macrophage Inflammation through Nicotinamide Adenine Dinucleotide Phosphate Homeostasis and Protects against Atherosclerosis

Cited by 39 publications

References 31 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

The Crystal Structure of Six-transmembrane Epithelial Antigen of the Prostate 4 (Steap4), a Ferri/Cuprireductase, Suggests a Novel Interdomain Flavin-binding Site

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

Contact Info

Product

Resources

About