Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein.

RBP4 (plasma retinol-binding protein) is the 21 kDa transporter of all-trans retinol that circulates in plasma as a moderately tight 1:1 molar complex of the vitamin with the protein. RBP4 is primarily synthesized in the liver but is also produced by adipose tissue and circulates bound to a larger protein, transthyretin, TTR, that serves to increase its molecular mass and thus avoid its elimination by glomerular filtration. This paper reports the high resolution three-dimensional structures of human RBP4 naturally lacking bound retinol purified from plasma, urine and amniotic fluid. In all these crystals we found a fatty acid molecule bound in the hydrophobic ligand-binding site, a result confirmed by mass spectrometry measurements. In addition we also report the 1.5 Šresolution structures of human holo-RBP4 and of the protein saturated with palmitic and lauric acid and discuss the interaction of the fatty acids and retinol with the protein.

Cardiac transplantation in transthyretin amyloid cardiomyopathy: Outcomes from three decades of tertiary center experience.

Aims: Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced ATTR-CM are limited to cardiac transplantation (CT). Despite case series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be a contraindication to CT in some centers, partly due to a perceived risk of amyloid recurrence in the allograft. We report long-term outcomes of CT in ATTR-CM at two tertiary centers. Materials and methods and Results: We retrospectively evaluated ATTR-CM patients across two tertiary centers who underwent transplantation between 1990 and 2020. Pre-transplantation characteristics were determined and outcomes were compared with a cohort of non-transplanted ATTR-CM patients. Fourteen (12 male, 2 female) patients with ATTR-CM underwent CT including 11 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 62 years and median follow up post-CT was 66 months. One, three, and five-year survival was 100, 92, and 90%, respectively and the longest surviving patient was Censored > 19 years post CT. No patients had recurrence of amyloid in the cardiac allograft. Four patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly prolonged compared to UK patients with ATTR-CM generally (p < 0.001) including those diagnosed under age 65 years (p = 0.008) or with early stage cardiomyopathy (p < 0.001). Conclusion: CT is well-tolerated, restores functional capacity and improves prognosis in ATTR-CM. The risk of amyloid recurrence in the cardiac allograft appears to be low.

Surgically treated intradural spinal manifestation of hereditary amyloidogenic transthyretin amyloidosis - A case report and scoping review of the literature.

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal-dominant disorder, where a TTR mutations lead to amyloid fibril deposits in tissues and consecutively alter organ function. ATTRv is a multisystemic disorder with a heterogeneous clinical presentation. Spinal leptomeningeal depositions are described only scarcely in the literature. Research question: We present a rare case of surgically treated intradural, extra-medullary amyloidosis with respective clinical, diagnostic and surgical features to raise awareness of this rare entity. Material and methods: Clinical, radiological and operative characteristics were retrieved from the electronical patient management system. Additionally, a scoping literature review on leptomeningeal spinal manifestations of ATTRv was performed. Results: A 45-year-old man with a known ATTRv presented with gait disturbance and paresis of the lower extremities. He had been treated with the siRNA therapeutical Patisiran for 13 months under which his symptoms worsened. An MRI of the spine revealed spinal cord compression with myelopathy at the level of T2 with anterior dislocation of the spinal cord due to an intradural, extramedullary lesion. A laminectomy and opening of the dura with a complete resection of the lesion was performed. The histological examination of the biopsy showed amyloid deposits. At six-month follow-up the patient showed complete normalization of the paresis, gait, sensory and urinary disturbances and resumed his work. Discussion and conclusion: Spinal leptomeningeal deposition of amyloid is a rare occurrence within the framework of ATTRv. Micro-neurosurgical complete resection of the lesion is feasible in patients with preoperative myelopathic symptoms and resulted in complete symptom relief in this case.

Mitosis of hepatitis B virus-infected cells in vitro results in uninfected daughter cells.

Background & Aims: The chronicity of HBV (and resultant liver disease) is determined by intrahepatic persistence of the HBV covalently closed circular DNA (cccDNA), an episomal form that encodes all viral transcripts. Therefore, cccDNA is a key target for new treatments, with the ultimate therapeutic aim being its complete elimination. Although established cccDNA molecules are known to be stable in resting hepatocytes, we aimed to understand their fate in dividing cells using in vitro models. Methods: We infected HepG2-NTCP and HepaRG-NTCP cells with HBV and induced mitosis by passaging cells. We measured cccDNA copy number (by precise PCR assays) and HBV-expressing cells (by immunofluorescence) with wild-type HBV. We used reporter viruses expressing luciferase or RFP to track number of HBV-expressing cells over time after mitosis induction using luciferase assays and live imaging, respectively. Results: In all cases, we observed dramatic reductions in cccDNA levels, HBV-positive cell numbers, and cccDNA-dependent protein expression after each round of cell mitosis. The rates of reduction were highly consistent with mathematical models of a complete cccDNA loss in (as opposed to dilution into) daughter cells. Conclusions: Our results are concordant with previous animal models of HBV infection and show that HBV persistence can be efficiently overcome by inducing cell mitosis. These results support therapeutic approaches that induce liver turnover (e.g. immune modulators) in addition to direct-acting antiviral therapies to achieve hepatitis B cure. Lay summary: Chronic hepatitis B affects 300 million people (killing 884,000 per year) and is incurable. To cure it, we need to clear the HBV genome from the liver. In this study, we looked at how the virus behaves after a cell divides. We found that it completely clears the virus, making 2 new uninfected cells. Our work informs new approaches to develop cures for chronic hepatitis B infections.

Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

Translation of New and Emerging Therapies for Genetic Cardiomyopathies.

The primary etiology of a diverse range of cardiomyopathies is now understood to be genetic, creating a new paradigm for targeting treatments on the basis of the underlying molecular cause. This review provides a genetic and etiologic context for the traditional clinical classifications of cardiomyopathy, including molecular subtypes that may exhibit differential responses to existing or emerging treatments. The authors describe several emerging cardiomyopathy treatments, including gene therapy, direct targeting of myofilament function, protein quality control, metabolism, and others. The authors discuss advantages and disadvantages of these approaches and indicate areas of high potential for short- and longer term efficacy.

Organophosphate esters cause thyroid dysfunction via multiple signaling pathways in zebrafish brain.

Organophosphate esters (OPEs) are widespread in various environmental media, and can disrupt thyroid endocrine signaling pathways. Mechanisms by which OPEs disrupt thyroid hormone (TH) signal transduction are not fully understood. Here, we present in vivo-in vitro-in silico evidence establishing OPEs as environmental THs competitively entering the brain to inhibit growth of zebrafish via multiple signaling pathways. OPEs can bind to transthyretin (TTR) and thyroxine-binding globulin, thereby affecting the transport of TH in the blood, and to the brain by TTR through the blood-brain barrier. When GH3 cells were exposed to OPEs, cell proliferation was significantly inhibited given that OPEs are competitive inhibitors of TH. Cresyl diphenyl phosphate was shown to be an effective antagonist of TH. Chronic exposure to OPEs significantly inhibited the growth of zebrafish by interfering with thyroperoxidase and thyroglobulin to inhibit TH synthesis. Based on comparisons of modulations of gene expression with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, signaling pathways related to thyroid endocrine functions, such as receptor-ligand binding and regulation of hormone levels, were identified as being affected by exposure to OPEs. Effects were also associated with the biosynthesis and metabolism of lipids, and neuroactive ligand-receptor interactions. These findings provide a comprehensive understanding of the mechanisms by which OPEs disrupt thyroid pathways in zebrafish.

Effect of Tafamidis on Serum Transthyretin Levels in Non-Trial Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is slowed by tafamidis, which stabilizes the TTR molecule and reduces the formation of amyloidogenic oligomers. Stabilizers in clinical doses raise serum TTR, which may be a surrogate for the degree of stabilization. OBJECTIVES: This study aims to determine, in a non-trial, unselected population of patients with ATTR cardiomyopathy, the effect of tafamidis on serum levels of TTR, and to compare these with published data of changes in TTR. METHODS: TTR levels were measured before therapy and 3 to 12 months following initiation of tafamidis therapy in all patients seen between May 20, 2019, and March 1, 2021, who had a follow-up visits within 12 months of therapy initiation. RESULTS: Among 72 patients with ATTR cardiomyopathy (67 patients with wild-type and 5 patients with variant TTR), administration of tafamidis increased serum TTR from 21.8 mg ± 0.7 mg/dL to 29.3 ± 0.86 mg/dL, an increase of 34.5%. In 5 patients with variant TTR, the increase was 70.9%, compared to 32.0% in the wild-type patients. Mean N-terminal pro-brain natriuretic peptide increased over a mean follow-up of 21 ± 1.2 weeks, but the change was not statistically significant. Over the same period there was a small increase in high-sensitivity troponin T that was of borderline statistical significance (P = 0.057). CONCLUSIONS: Tafamidis consistently increases serum TTR levels in patients with ATTR cardiomyopathy, consistent with its effect on stabilizing TTR. Measurement of TTR level change post-TTR stabilizing therapy might be a surrogate for stabilization and could be a more accurate measure of drug efficacy than an in vitro nonphysiologic test of stabilization.

Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records.

BACKGROUND: New treatments for transthyretin amyloidosis improve survival, but diagnosis remains challenging. Pathogenic or likely pathogenic (P/LP) variants in the transthyretin (TTR) gene are one cause of transthyretin amyloidosis, and genomic screening has been proposed to identify at-risk individuals. However, data on disease features and penetrance are lacking to inform the utility of such population-based genomic screening for TTR. OBJECTIVES: This study characterized the prevalence of P/LP variants in TTR identified through exome sequencing and the burden of associated disease from electronic health records for individuals with these variants from a large (N = 134,753), primarily European-ancestry cohort. METHODS: We compared frequencies of common disease features and cardiac imaging findings between individuals with and without P/LP TTR variants. RESULTS: We identified 157 of 134,753 (0.12%) individuals with P/LP TTR variants (43% male, median age 52 [Q1-Q3: 37-61] years). Seven P/LP variants accounted for all observations, the majority being V122I (p.V142I; 113, 0.08%). Approximately 60% (n = 91) of individuals with P/LP TTR variants (all V122I) had African ancestry. Diagnoses of amyloidosis were limited (2 of 157 patients), although related heart disease diagnoses, including cardiomyopathy and heart failure, were significantly increased in individuals with P/LP TTR variants who were aged >60 years. Fourteen percent (7 of 49) of individuals aged ≥60 or older with a P/LP TTR variant had heart disease and ventricular septal thickness >1.2 cm, only one of whom was diagnosed with amyloidosis. CONCLUSIONS: Individuals with P/LP TTR variants identified by genomic screening have increased odds of heart disease after age 60 years, although amyloidosis is likely underdiagnosed without knowledge of the genetic variant.

Temporal Trends of Wild-Type Transthyretin Amyloid Cardiomyopathy in the Transthyretin Amyloidosis Outcomes Survey.

BACKGROUND: Transthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations. OBJECTIVES: This study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS. METHODS: Using THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy. RESULTS: There were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015-2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%). CONCLUSIONS: In the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745).

Amyloid fibril formation is suppressed in microgravity.

In the future, humans may live in space because of global pollution and weather fluctuations. In microgravity, convection does not occur, which may change the amyloidogenicity of proteins. However, the effect of gravity on amyloid fibril formation is unclear and remains to be elucidated. Here, we analyzed the effect of microgravity on amyloid fibril formation of amyloidogenic proteins including insulin, amyloid ß42 (Aß42), and transthyretin (TTR). We produced microgravity (10-3 g) by using the gravity controller Gravite. Human insulin, Aß42, and human wild-type TTR (TTRwt) were incubated at pH 3.0, 7.0, and 3.5 at 37 °C, respectively, in 1 g on the ground or in microgravity. We measured amyloidogenicity via the thioflavin T (ThT) method and cell-based 1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyryl]benzene (FSB) assay. ThT fluorescence intensity and cell-based FSB assay results for human insulin samples were decreased in microgravity compared with results in 1 g. Aß42 samples did not differ in ThT fluorescence intensity in microgravity and in 1 g on the ground. However, in the cell-based FSB assay, the staining intensity was reduced in microgravity compared with that on 1 g. Human TTRwt tended to form fewer amyloid fibrils in ThT fluorescence intensity and cell-based FSB assays in microgravity than in 1 g. Human insulin and Aß42 showed decreased amyloid fibril formation in microgravity compared with that in 1 g. Human TTRwt tended to form fewer amyloid fibrils in microgravity. Our experiments suggest that the earth's gravity may be an accelerating factor for amyloid fibril formation.

Concomitant Transthyretin Amyloidosis and Severe Aortic Stenosis in Elderly Indian Population: A Pilot Study.

BACKGROUND: Prevalence of both degenerative severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR-CA) increases with age. Dual disease (AS+myocardial ATTR-CA) occurs in significant proportion of patients undergoing surgical aortic valve replacement (SAVR). OBJECTIVES: This study aimed to determine the prevalence of ATTR-CA in severe AS in the Indian population, identify noninvasive predictors of its diagnosis, and understand its impact on prognosis. METHODS: Symptomatic severe AS patients aged ≥65 years undergoing SAVR were enrolled. ATTR-CA diagnosis was based on preoperative 99m-technetium pyrophosphate (PYP) scan and intraoperatively obtained basal interventricular septum biopsy for myocardial ATTR-CA, and excised native aortic valve for isolated valvular ATTR-CA. Primary amyloidosis was excluded by serum/urine protein electrophoresis with serum immunofixation. RESULTS: SAVR was performed in 46 AS patients (age 70 ± 5 years, 70% men). PYP scan was performed for 32 patients, with significant PYP uptake in 3 (n = 3 of 32, 9.4%), suggestive of myocardial ATTR-CA. On histopathological examination, none of the interventricular septum biopsy specimens had amyloid deposits, whereas 33 (71.7%) native aortic valves showed amyloid deposits, of which 19 (57.6%) had transthyretin deposition suggestive of isolated valvular amyloidosis. Noninvasive markers of dual disease included low myocardial contraction fraction (median [interquartile range], 28.8% [23.8% to 39.1%] vs 15.3% [9.3% to 16.1%]; P = 0.006), deceleration time (215 [144 to 236] ms vs 88 [60 to 106] ms; P = 0.009) and global longitudinal strain (-18.7% [-21.1% to -16.9%] vs -14.2% [-17.0% to -9.7%]; P = 0.030). At 1-year follow-up, 2 patients died (4.3%); 1 each in myocardial ATTR-CA negative and positive groups (3.4% vs 33.3%; P = 0.477). CONCLUSIONS: Dual disease is not uncommon in India. Isolated valvular amyloidosis in severe AS is much more common.

Recent developments in the medicinal chemistry of single boron atom-containing compounds.

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.

Novel vectors and approaches for gene therapy in liver diseases.

Gene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Herein, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarise some of the limitations of current liver-directed gene therapy approaches and potential ways of overcoming them.

Our emerging understanding of the roles of long non-coding RNAs in normal liver function, disease, and malignancy.

Long non-coding RNAs (lncRNAs) are important biological mediators that regulate numerous cellular processes. New experimental evidence suggests that lncRNAs play essential roles in liver development, normal liver physiology, fibrosis, and malignancy, including hepatocellular carcinoma and cholangiocarcinoma. In this review, we summarise our current understanding of the function of lncRNAs in the liver in both health and disease, as well as discuss approaches that could be used to target these non-coding transcripts for therapeutic purposes.

Early-Onset of Transthyretin Amyloidosis in a Young Afro-Caribbean Woman With Thr60Ala Mutation.

Transthyretin amyloidosis involves the deposition of transthyretin amyloid fibrils in the body. We report an unusual case of a young Afro-Caribbean woman harboring a Thr60Ala mutation who presented with clinical signs of heart failure and polyneuropathy confirmed with genetic testing and results of an abdominal fat pad biopsy. (Level of Difficulty: Intermediate.).

Subthreshold Aortic Valve Calcium Scores in Severe Aortic Stenosis and Transthyretin Cardiac Amyloidosis.

We have clinically observed that some patients with transthyretin cardiac amyloidosis and severe aortic stenosis may have lesser degrees of calcification than one might expect. We report a case series of 3 patients with transthyretin cardiac amyloidosis and severe aortic stenosis despite discordant aortic valve calcium scores. (Level of Difficulty: Intermediate.).

Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant.

Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The ligands investigated were the drug candidate AG10 and its decarboxy and N-methyl derivatives along with the drug tafamidis. These ligands bound to the receptor in two halogen binding pockets (HBP) designated AB and A'B'. Inter-ligand distances, solvent accessible surface areas, root mean squared deviation measurements, and extracted structures showed very little change in the AG10 ligands' conformations or locations within the HBP during the MD simulation. In addition, the AG10 ligands experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in both the AB and A'B' binding pockets and Lysine-15 residues found near the surface of the receptor. Distance measurements showed these H-bonds formed simultaneously during the MD simulation. Removal of the AG10 carboxylate functional group to form decarboxy-AG10 disrupted this two-point interaction causing the ligand in the AB pocket to undergo a conformational change during the MD simulation. Likewise, addition of a methyl group to the AG10 hydrazone functional group also disrupted the two-point interaction by decreasing hydrogen bonding interactions with the receptor. Finally, MD simulations showed that the tafamidis ligands experienced fewer hydrogen bonding interactions than AG10 with the protein receptor. The tafamidis ligand in pocket A'B' was also found to move deeper into the HBP during the MD simulation.

Best Practices for Prognostic Evaluation of a Patient With Transthyretin Amyloid Cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) has emerged as an increasingly identified etiology of heart failure. Fortunately, the disease now has an approved therapy, with many others under development. Assessment of prognosis in ATTR-CM is critical to inform patients about the disease course and guide clinical decisions. This review discusses the evidence behind clinical, biomarker, and imaging findings that inform prognosis in patients with ATTR-CM and can assist providers in the shared decision-making process during management of this disease.

Vitamin A in regulation of insulin responsiveness: mini review.

Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples 'sensing' of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.