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Signaling by retinol and its serum binding protein.

ABSTRACT: Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP) which, in turn, associates with transthyretin (TTR) to form a retinol-RBP-TTR ternary complex. At some tissues, retinol-bound (holo-) RBP is recognized by a membrane protein termed STRA6, which transports retinol from extracellular RBP into cells and, concomitantly, activates a JAK2/STAT3/5 signaling cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signaling are critically inter-dependent, and they both require the presence of cellular retinol-binding protein 1 (CRBP1), an intracellular retinol acceptor, as well as a retinol-metabolizing enzyme such as lecithin:retinol acyltransferase (LRAT). STRA6 thus functions as a "cytokine signaling transporter" which couples vitamin A homeostasis and metabolism to cell signaling, thereby regulating gene transcription. Recent studies provided molecular level insights into the mode of action of this unique protein.

SUBMITTER: Noy N

PROVIDER: S-EPMC4323939 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Signaling by retinol and its serum binding protein.

Noy Noa N

Prostaglandins, leukotrienes, and essential fatty acids 20141029

Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP) which, in turn, associates with transthyretin (TTR) to form a retinol-RBP-TTR ternary complex. At some tissues, retinol-bound (holo-) RBP is recognized by a membrane protein termed STRA6, which transports retinol from extracellular RBP into cells and, concomitantly, activates a JAK2/STAT3/5 signaling cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signaling are crit ...[more]

PMID: 25481334

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Project description:Importance:Transthyretin cardiac amyloidosis (ATTR) is an underrecognized cause of heart failure (HF) in older individuals, owing in part to difficulty in diagnosis. ATTR can result from substitution of valine for isoleucine at codon 122 of the transthyretin (TTR) gene (V122I), present in 3.43% of African American individuals. Objective:To examine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis. Design, Setting, and Participants:In this combined prospective and retrospective cohort study performed at a tertiary care referral center, 50 African American patients 60 years or older with nonamyloid HF and cardiac wall thickening prospectively genotyped from September 1, 2014, through December 31, 2015, and a comparator cohort of 25 patients with biopsy-proven ATTR V122I amyloidosis recruited from September 1, 2009, through November 31, 2014, comprised the development cohort. Twenty-seven African American patients and 9 patients with ATTR V122I amyloidosis comprised the validation cohort. Main Outcomes and Measures:Circulating RBP4, TTR, B-type natriuretic peptide (BNP), and troponin I (TnI) concentrations and electrocardiographic, echocardiographic, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls. Results:Age, sex, and BNP and TnI concentrations were similar between the 25 patients with ATTR V122I amyloidosis (mean [SD] age, 72.2 [7.4] years; 18 male [72%]) and the 50 controls (mean [SD] age, 69.2 [5.7] years; 31 male [62%]). Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared with nonamyloid controls (31.5 vs 49.4 µg/mL, P?<?.001), and the difference persisted after controlling for potential confounding variables. Left ventricular ejection fraction was lower in patients with ATTR V122I amyloidosis (mean [SD], 40% [14%] vs 57% [14%], P?<?.001), whereas interventricular septal diameter was higher (mean [SD], 16 [3] vs 14 [2] mm, P?<?.001). The ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (area under the curve [AUC]?=?0.78; 95% CI, 0.67-0.88). A clinical prediction algorithm composed of RBP4, TTR, left ventricular ejection fraction, interventricular septal diameter, mean limb lead QRS voltage, and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC?=?0.97; 95% CI, 0.93-1.00), whereas a 4-parameter model, including RBP4 concentration, retained excellent discrimination (AUC?=?0.92; 95% CI, 0.86-0.99). The models maintained excellent discrimination in the validation cohort. Conclusions and Relevance:A prediction model using circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloidosis from nonamyloid HF in a case-matched cohort. This clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly African American patients with HF.

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Signaling by retinol and its serum binding protein.

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Signaling by retinol and its serum binding protein.

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