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Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.

ABSTRACT: Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in integrating inflammatory and metabolic responses and thus plays a key role in systemic metabolic homeostasis.

SUBMITTER: Wellen KE

PROVIDER: S-EPMC2408881 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.

Wellen Kathryn E KE Fucho Raquel R Gregor Margaret F MF Furuhashi Masato M Morgan Carlos C Lindstad Torstein T Vaillancourt Eric E Gorgun Cem Z CZ Saatcioglu Fahri F Hotamisligil Gökhan S GS

Cell 20070501 3

Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of ...[more]

PMID: 17482547

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Project description:BACKGROUND: Iron and its homeostasis are intimately related to inflammatory responses, but the underlying molecular mechanisms are poorly understood. We investigated the role of Steap3 in regulating iron homeostasis in macrophages, and the effects of Steap3 depletion on host inflammatory responses. DESIGN AND METHODS: We analyzed bone marrow-derived macrophages and primary cultured hepatocytes from Steap3(-/-) mouse models to investigate the roles of Steap3 in coordinately regulating iron homeostasis and inflammatory responses. First, we examined iron distribution and iron status in cells deficient in Steap3, as well as the requirement for the Steap3 gene during inflammatory responses. Secondly, we analyzed the regulation of Steap3 expression by inflammatory stimuli and thus, the influence of these stimuli on iron distribution and homeostasis. RESULTS: We found that Steap3 mRNA was expressed at high levels in macrophages and hepatocytes. Steap3 deficiency led to impaired iron homeostasis, causing abnormal iron distribution and a decreased availability of cytosolic iron in macrophages. Among STEAP family members, Steap3 mRNA was uniquely down-regulated in macrophages stimulated by lipopolysaccharides. To determine whether Steap3 regulated iron homeostasis during inflammatory stress, we treated Steap3(-/-) mice with lipopolysaccharide, which produced greater iron accumulation in the vital tissues of these mice compared to in the tissues of wild-type controls. Furthermore, Steap3 depletion led to impaired induction of interferon-?, monocyte chemoattractant protein-5, and interferon induced protein-10 in macrophages via the TLR4-mediated signaling pathway. CONCLUSIONS: Steap3 is important in regulating both iron homeostasis and TLR4-mediated inflammatory responses in macrophages. Steap3 deficiency causes abnormal iron status and homeostasis, which leads to impaired TLR4-mediated inflammatory responses in macrophages. Following inflammatory stimuli, Steap3 depletion causes dysregulated iron sequestration and distribution. Our results provide important insights into the function of Steap3 as a coordinate regulator of both iron homeostasis and innate immunity.

Project description:Maintaining an optimal level of chromosomal supercoiling is critical for the progression of DNA replication and transcription. Moreover, changes in global supercoiling affect the expression of a large number of genes and play a fundamental role in adapting to stress. Topoisomerase I (TopA) and gyrase are key players in the regulation of bacterial chromosomal topology through their respective abilities to relax and compact DNA. Soil bacteria such as Streptomyces species, which grow as branched, multigenomic hyphae, are subject to environmental stresses that are associated with changes in chromosomal topology. The topological fluctuations modulate the transcriptional activity of a large number of genes and in Streptomyces are related to the production of antibiotics. To better understand the regulation of topological homeostasis in Streptomyces coelicolor, we investigated the interplay between the activities of the topoisomerase-encoding genes topA and gyrBA We show that the expression of both genes is supercoiling sensitive. Remarkably, increased chromosomal supercoiling induces the topA promoter but only slightly influences gyrBA transcription, while DNA relaxation affects the topA promoter only marginally but strongly activates the gyrBA operon. Moreover, we showed that exposure to elevated temperatures induces rapid relaxation, which results in changes in the levels of both topoisomerases. We therefore propose a unique mechanism of S. coelicolor chromosomal topology maintenance based on the supercoiling-dependent stimulation, rather than repression, of the transcription of both topoisomerase genes. These findings provide important insight into the maintenance of topological homeostasis in an industrially important antibiotic producer.ImportanceWe describe the unique regulation of genes encoding two topoisomerases, topoisomerase I (TopA) and gyrase, in a model Streptomyces species. Our studies demonstrate the coordination of topoisomerase gene regulation, which is crucial for maintenance of topological homeostasis. Streptomyces species are producers of a plethora of biologically active secondary metabolites, including antibiotics, antitumor agents, and immunosuppressants. The significant regulatory factor controlling the secondary metabolism is the global chromosomal topology. Thus, the investigation of chromosomal topology homeostasis in Streptomyces strains is crucial for their use in industrial applications as producers of secondary metabolites.

Project description:Central nervous system (CNS) invasion during acute-stage HIV-infection has been demonstrated in a small number of individuals, but there is no evidence of neurological impairment at this stage and virus infection in brain appears to be controlled until late-stage disease. Using our reproducible SIV macaque model to examine the earliest stages of infection in the CNS, we identified immune responses that differentially regulate inflammation and virus replication in the brain compared to the peripheral blood and lymphoid tissues. SIV replication in brain macrophages and in brain of SIV-infected macaques was detected at 4 days post-inoculation (p.i.). This was accompanied by upregulation of innate immune responses, including IFNbeta, IFNbeta-induced gene MxA mRNA, and TNFalpha. Additionally, IL-10, the chemokine CCL2, and activation markers in macrophages, endothelial cells, and astrocytes were all increased in the brain at four days p.i. We observed synchronous control of virus replication, cytokine mRNA levels and inflammatory markers (MHC Class II, CD68 and GFAP) by 14 days p.i.; however, control failure was followed by development of CNS lesions in the brain. SIV infection was accompanied by induction of the dominant-negative isoform of C/EBPbeta, which regulates SIV, CCL2, and IL6 transcription, as well as inflammatory responses in macrophages and astrocytes. This synchronous response in the CNS is in part due to the effect of the C/EBPbeta on virus replication and cytokine expression in macrophage-lineage cells in contrast to CD4+ lymphocytes in peripheral blood and lymphoid tissues. Thus, we have identified a crucial period in the brain when virus replication and inflammation are controlled. As in HIV-infected individuals, though, this control is not sustained in the brain. Our results suggest that intervention with antiretroviral drugs or anti-inflammatory therapeutics with CNS penetration would sustain early control. These studies further suggest that interventions should target HIV-infected individuals with increased CCL2 levels or HIV RNA in the CNS.

Dataset Information

Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.

Publications

Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.

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