Biological Functions of RBP4 and Its Relevance for Human Diseases

Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body's vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4's actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases

Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis

The tumor suppressor p53 is involved in the adaptation of hepatic metabolism to nutrient availability. Acute deletion of p53 in the mouse liver affects hepatic glucose and triglyceride metabolism. However, long-term adaptations upon the loss of hepatic p53 and its transcriptional regulators are unknown. Here we show that short-term, but not chronic, liver-specific deletion of p53 in mice reduces liver glycogen levels, and we implicate the transcription factor forkhead box O1 protein (FOXO1) in the regulation of p53 and its target genes. We demonstrate that acute p53 deletion prevents glycogen accumulation upon refeeding, whereas a chronic loss of p53 associates with a compensational activation of the glycogen synthesis pathway. Moreover, we identify fasting-activated FOXO1 as a repressor of p53 transcription in hepatocytes. We show that this repression is relieved by inactivation of FOXO1 by insulin, which likely mediates the upregulation of p53 expression upon refeeding. Strikingly, we find that high-fat diet-induced insulin resistance with persistent FOXO1 activation not only blunted the regulation of p53 but also the induction of p53 target genes like p21 during fasting, indicating overlapping effects of both FOXO1 and p53 on target gene expression in a context-dependent manner. Thus, we conclude that p53 acutely controls glycogen storage in the liver and is linked to insulin signaling via FOXO1, which has important implications for our understanding of the hepatic adaptation to nutrient availability

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations

Detection of group a streptococcal pharyngitis by quantitative PCR.

Group A streptococcus (GAS) is the most common bacterial cause of sore throat. School-age children bear the highest burden of GAS pharyngitis. Accurate diagnosis is difficult: the majority of sore throats are viral in origin, culture-based identification of GAS requires 24-48 hours, and up to 15% of children are asymptomatic throat carriers of GAS. The aim of this study was to develop a quantitative polymerase chain reaction (qPCR) assay for detecting GAS pharyngitis and assess its suitability for clinical diagnosis.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe

OBJECTIVE: In 2014 the European Union-funded E-PILEPSY project was launched to improve awareness of, and accessibility to, epilepsy surgery across Europe. We aimed to investigate the current use of neuroimaging, electromagnetic source localization, and imaging postprocessing procedures in participating centers. METHODS: A survey on the clinical use of imaging, electromagnetic source localization, and postprocessing methods in epilepsy surgery candidates was distributed among the 25 centers of the consortium. A descriptive analysis was performed, and results were compared to existing guidelines and recommendations. RESULTS: Response rate was 96%. Standard epilepsy magnetic resonance imaging (MRI) protocols are acquired at 3 Tesla by 15 centers and at 1.5 Tesla by 9 centers. Three centers perform 3T MRI only if indicated. Twenty-six different MRI sequences were reported. Six centers follow all guideline-recommended MRI sequences with the proposed slice orientation and slice thickness or voxel size. Additional sequences are used by 22 centers. MRI postprocessing methods are used in 16 centers. Interictal positron emission tomography (PET) is available in 22 centers; all using 18F-fluorodeoxyglucose (FDG). Seventeen centers perform PET postprocessing. Single-photon emission computed tomography (SPECT) is used by 19 centers, of which 15 perform postprocessing. Four centers perform neither PET nor SPECT in children. Seven centers apply magnetoencephalography (MEG) source localization, and nine apply electroencephalography (EEG) source localization. Fourteen combinations of inverse methods and volume conduction models are used. SIGNIFICANCE: We report a large variation in the presurgical diagnostic workup among epilepsy surgery centers across Europe. This diversity underscores the need for high-quality systematic reviews, evidence-based recommendations, and harmonization of available diagnostic presurgical methods