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JAK-STAT in lipid metabolism of adipocytes.

ABSTRACT: JAK-STAT signaling pathway plays an important role in the cells' development and homeostasis. Over the past decades, the studies have identified the role of the JAK-STAT pathway in cell proliferation and apoptosis. Here, we want to discuss that whether and how the JAK-STAT pathway affects the lipid metabolism of adipose tissue. A host of cytokines and hormones can regulate lipid metabolism through activating the JAK-STAT signaling pathway. Activated STATs can regulate lipid metabolism directly by influencing the expression of enzymes. We have summarized the relevant research and articles of JAK-STAT during the recent years. Within this review, we will introduce you the recent research and highlight the unresolved problems in understanding how JAK-STAT signaling pathway contribute to the lipid metabolism in mature adipocytes and preadipocytes. Dysregulation of the JAK-STAT pathway would lead to a multiple metabolism disorders and medicines for this signaling pathway maybe become a new idea for diseases such as metabolic syndrome, especially in children.

SUBMITTER: Xu D

PROVIDER: S-EPMC3906428 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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JAK-STAT in lipid metabolism of adipocytes.

Xu Dong D Yin Chunyan C Wang Sisi S Xiao Yanfeng Y

JAK-STAT 20131001 4

JAK-STAT signaling pathway plays an important role in the cells' development and homeostasis. Over the past decades, the studies have identified the role of the JAK-STAT pathway in cell proliferation and apoptosis. Here, we want to discuss that whether and how the JAK-STAT pathway affects the lipid metabolism of adipose tissue. A host of cytokines and hormones can regulate lipid metabolism through activating the JAK-STAT signaling pathway. Activated STATs can regulate lipid metabolism directly b ...[more]

PMID: 24498541

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Project description:BackgroundThe JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.Methods & findingsWe used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.ConclusionsAminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

Dataset Information

JAK-STAT in lipid metabolism of adipocytes.

Publications

JAK-STAT in lipid metabolism of adipocytes.

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