Retinol transfer across and between phospholipid bilayer membranes

Fex, Göran; Johannesson, Gunvor

doi:10.1016/0005-2736(88)90438-5

Cited by 64 publications

(33 citation statements)

References 33 publications

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“…1h). The observations thus support the previously proposed model whereby supply of ROH from circulating holo-RBP or holo-RBP-TTR to cells occurs primarily by diffusion through the plasma membranes (10,14,20,21). Taken together with the observations that ROH transport by STRA6 is critical for enabling activation of STRA6 signaling (5), the data indicate that, with the exception of the eye (26), the main role of ROH transport by STRA6 is not to provide the vitamin to cells but to couple sensing of circulating free holo-ROH levels to cell signaling.…”

Section: Discussionsupporting

confidence: 89%

“…It was proposed that, due to its hydrophobic nature, ROH can readily move from extracellular RBP into cells by diffusion across the plasma membranes at fluxes that are dictated by its extracellular-to-intracellular concentration gradient (10,14,20,21). However, it has also been suggested that uptake of ROH from circulating holo-RBP is mediated by a cell surface receptor (13,28).…”

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confidence: 99%

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Transthyretin Blocks Retinol Uptake and Cell Signaling by the Holo-Retinol-Binding Protein Receptor STRA6

Berry

Croniger

Ghyselinck

et al. 2012

Molecular and Cellular Biology

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c Vitamin A is secreted from cellular stores and circulates in blood bound to retinol-binding protein (RBP). In turn, holo-RBP associates in plasma with transthyretin (TTR) to form a ternary RBP-retinol-TTR complex. It is believed that binding to TTR prevents the loss of RBP by filtration in the kidney. At target cells, holo-RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it mediates uptake of retinol from extracellular RBP into cells, and it functions as a cytokine receptor that, upon binding holo-RBP, triggers a JAK/STAT signaling cascade. We previously showed that STRA6-mediated signaling underlies the ability of RBP to induce insulin resistance. However, the role that TTR, the binding partner of holo-RBP in blood, plays in STRA6-mediated activities remained unknown. Here we show that TTR blocks the ability of holo-RBP to associate with STRA6 and thereby effectively suppresses both STRA6-mediated retinol uptake and STRA6-initiated cell signaling. Consequently, TTR protects mice from RBP-induced insulin resistance, reflected by reduced phosphorylation of insulin receptor and glucose tolerance tests. The data indicate that STRA6 functions only under circumstances where the plasma RBP level exceeds that of TTR and demonstrate that, in addition to preventing the loss of RBP, TTR plays a central role in regulating holo-RBP/ STRA6 signaling. V itamin A (retinol [ROH]) plays critical roles both in the embryo and in the adult, where it regulates multiple cellular processes and is essential for embryonic development, reproduction, immune function, and vision (29,32,33). The vitamin exerts many of its biological activities by giving rise to active metabolites: the visual chromophore 11-cis-retinaldehyde and retinoic acid (RA), which regulates gene transcription by activating specific nuclear receptors (11,27). ROH is stored in various tissues, including white adipose tissue (WAT), lung, and retinal pigment epithelium in the eye, but its main storage site is the liver. ROH is secreted from storage into the circulation bound to retinol-binding protein (RBP), a 21-kDa polypeptide that contains one binding site for ROH. In most mammals, ROH-bound RBP (holo-RBP) does not circulate alone but is associated with another protein called transthyretin (TTR), a 56-kDa homotetramer that, in addition to associating with RBP, functions as a carrier for thyroid hormones (23,24). ROH thus reaches target tissues bound in a holo-RBP-TTR complex that, under normal circumstances, displays a 1:1 molar stoichiometry. It is believed that binding of RBP to TTR serves to prevent the loss of the smaller protein from blood by filtration in the glomeruli. The concentration of the holo-RBP-TTR complex in plasma is kept constant at 1 to 2 M except in extreme cases of vitamin A deficiency or in disease states. Notably, RBP levels are markedly elevated in blood of obese mice and humans, and it was reported that, under these circumstances, the protein induces insulin resistance (35).Association with the TTR-RBP complex al...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Transthyretin Blocks Retinol Uptake and Cell Signaling by the Holo-Retinol-Binding Protein Receptor STRA6

Berry

Croniger

Ghyselinck

et al. 2012

Molecular and Cellular Biology

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“…Clearly, although much has been accomplished, much remains to be done. If recent studies are any indicator, then more and more future studies will be devoted to the transfer behavior of lipid compounds that are of nutritional [148][149][150][151][152] and pharmacologic interest [153][154]. Free energy diagram of fluorescent PC partitioning between liquid-crystalline PC small unilamellar vesicles and water.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous lipid transfer between organized lipid assemblies

Brown

1992

Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes

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“…It was shown further that binding to RBP is not required for movement of retinol into or out of cells [45][46][47]. It was thus proposed that cellular uptake of retinol from RBP in blood occurs spontaneously and simply follows the concentration gradients of free retinol [45,46,[48][49][50]. In support of this model, reported rates of uptake of retinol by several target cells are two to three orders of magnitude lower than the rate of the spontaneous dissociation of retinol from RBP [51].…”

Section: Functions Of Rbpmentioning

confidence: 99%

Retinoid-binding proteins: mediators of retinoid action

2000

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Active vitamin A metabolites, known as retinoids, are essential for multiple physiological processes, ranging from vision to embryonic development. These small hydrophobic compounds associate in i o with soluble proteins that are present in a variety of cells and in particular extracellular compartments, and which bind different types of retinoids with high selectivity and affinity. Traditionally, retinoid-binding proteins were viewed as transport proteins that act by solubilizing and protecting their labile ligands in aqueous spaces. It is becoming increasingly clear, however, that, in addition to this general role, retinoid-binding proteins have diverse and specific functions in regulating the disposition, metabolism and activities of retinoids. Some retinoidbinding proteins appear to act by sequestering their ligands, thereby generating concentration gradients that allow cells to take up retinoids from extracellular pools and metabolic steps to

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Retinol transfer across and between phospholipid bilayer membranes

Cited by 64 publications

References 33 publications

Transthyretin Blocks Retinol Uptake and Cell Signaling by the Holo-Retinol-Binding Protein Receptor STRA6

Transthyretin Blocks Retinol Uptake and Cell Signaling by the Holo-Retinol-Binding Protein Receptor STRA6

Spontaneous lipid transfer between organized lipid assemblies

Retinoid-binding proteins: mediators of retinoid action

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