PHA-848125 br Acknowledgements This work was supported
Acknowledgements This work was supported by a grant from the Deutsche Forschungsgemeinschaft to Uwe Knippschild and Martin Wabitsch (SFB 1149/B4). P. Fischer-Posovszky is funded by a Margarete von Wrangell scholarship financed by the Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg, the European Social Fund, and the University of Ulm. We thank Roland Alberts, Julia Hofmann, and Elena Wurster for technical assistance.
Introduction Obesity-induced excess of adipose tissue storage capacity results in adipocyte dysfunction, leading to a lipolysis-mediated increased concentration of fatty acids (FA) in plasma , and induces the secretion of a wide range of adipose tissue-derived factors, including the fatty acid-binding protein 4 (FABP4) [, , ]. FABP4 is a 14-kDa cytosolic protein expressed in adipocytes , macrophages , and endothelial PHA-848125 , and increased circulating expression of FABP4 is linked with insulin resistance, type 2 diabetes and cardiovascular diseases . FABP4 reversibly binds to a single saturated or unsaturated long-chain FA with high affinity, transporting it intracellularly to the different cellular compartments . Under obesogenic conditions, FABP4 is actively released by adipocytes and acts as an adipokine , that is, a biologically active protein that can be taken up by different cell types, such as the endothelial cells . In addition to their role as an energy source, FA are also molecular signals. Therefore, FABP4 might play a key role in the regulation of lipid-mediated processes including the activation of inflammation and oxidative stress processes. Circulating FABP4 can modulate endothelial cell function. In fact, previous studies of our group have revealed that exogenous FABP4 (eFABP4) has a functional role in endothelial cells . Moreover, eFABP4 inhibits the activation of the insulin-signaling pathway, resulting in decreased eNOS activation and NO production inducing endothelial dysfunction , an event considered as the first process in the pathogenesis of atherosclerosis. However, the molecular mechanisms that regulate eFABP4 cellular uptake are still poorly understood. Consistently, in another study, we showed that cytokeratin 1 (CK1) and eFABP4 interact transiently in the membrane of endothelial cells , even though we did not evaluate the role of CK1 in the endocytosis of eFABP4 and its functional implication. Cytokeratins belong to a large family of intermediate filament proteins with cytoskeletal assembly properties . CK1, a basic-neutral type of cytokeratin, is found on the surface of endothelial cells, where it acts as a receptor-like protein . In endothelial cells, CK1 has been associated with urokinase plasminogen activator (uPAR) receptor as a multiprotein receptor for high-molecular-weight kininogen (HK), prekallikrein and 2-chain urokinase plasminogen . CK1 was also identified as a protein that facilitates endothelial internalization of myeloperoxidase  and c-reactive protein (CRP) .
Materials and methods
Discussion Although FABP4 was originally described as an intracellular protein affecting lipid fluxes, metabolism and signaling within cells, in recent years it has become evident that FABP4 can be actively released into the circulation where it acts as a critical mediator of metabolism and inflammatory processes through hormonal-like functions including among others, the regulation of hepatic glucose production . In fact, a large number of studies have shown that plasma levels of FABP4 are increased in obesity and type-2 diabetes , and that circulating FABP4 concentration correlated with clinical outcomes, such as body mass index, insulin resistance and dyslipidemia . Therefore, considering that plasma-circulating FABP4 can be taken up by several cell types and that eFABP4 is able to modulate its function, independently if receptor cells endogenously express FABP4, identifies the understanding of FABP4 cellular uptake mechanisms as a promising basis to develop effective therapeutic strategies against the pathogenesis of metabolic and vascular diseases.