How Free Retinol Behaves Differently from RBP-Bound Retinol in RBP Receptor-Mediated Vitamin A Uptake

Ming, Zhong; Kawaguchi, Riki; Kassai, Miki; Sun, Hui

doi:10.1128/mcb.01426-12

Cited by 10 publications

(11 citation statements)

References 23 publications

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“…49). The only identified receptor for this complex is Stra6 (63,130) that is expressed in the testis on Sertoli cells (7,36). However, it has been shown that the Stra6 receptor is not essential for maintaining vitamin A homeostasis in any tissue other than the eye, and Stra6deficient mice have normal fertility (7).…”

Section: Extrinsic Factor Controlling the A To A1 Spermatogonial mentioning

confidence: 99%

Spermatogenesis: The Commitment to Meiosis

Griswold

2016

Physiological Reviews

604

479

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Mammalian spermatogenesis requires a stem cell pool, a period of amplification of cell numbers, the completion of reduction division to haploid cells (meiosis), and the morphological transformation of the haploid cells into spermatozoa (spermiogenesis). The net result of these processes is the production of massive numbers of spermatozoa over the reproductive lifetime of the animal. One study that utilized homogenization-resistant spermatids as the standard determined that human daily sperm production (dsp) was at 45 million per day per testis (60). For each human that means ∼1,000 sperm are produced per second. A key to this level of gamete production is the organization and architecture of the mammalian testes that results in continuous sperm production. The seemingly complex repetitious relationship of cells termed the "cycle of the seminiferous epithelium" is driven by the continuous commitment of undifferentiated spermatogonia to meiosis and the period of time required to form spermatozoa. This commitment termed the A to A1 transition requires the action of retinoic acid (RA) on the undifferentiated spermatogonia or prospermatogonia. In stages VII to IX of the cycle of the seminiferous epithelium, Sertoli cells and germ cells are influenced by pulses of RA. These pulses of RA move along the seminiferous tubules coincident with the spermatogenic wave, presumably undergoing constant synthesis and degradation. The RA pulse then serves as a trigger to commit undifferentiated progenitor cells to the rigidly timed pathway into meiosis and spermatid differentiation.

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Section: Extrinsic Factor Controlling the A To A1 Spermatogonial mentioning

confidence: 99%

Spermatogenesis: The Commitment to Meiosis

Griswold

2016

Physiological Reviews

604

479

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“…So far, null mutations of RBP4 have not been characterized in humans ( Zhong et al, 2014 ), which may suggest that in contrast to mice, complete absence of RBP4 is incompatible with embryonic survival, regardless of maternal vitamin A intake. It is interesting to note that compared to rodents, humans seem to be much more sensitive to dysregulated retinoid homeostasis and retinoid toxicity associated with random retinoid diffusion ( Nau, 2001 ), which could be a likely consequence of dysfunctional RBP4 variants.…”

Section: Pathologies Associated With Rbp4 Mutations In Humansmentioning

confidence: 99%

Biological Functions of RBP4 and Its Relevance for Human Diseases

2021

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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.

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“…acknowledge the letter of Zhong et al (1). Our observations in references 2 to 5 demonstrated that, in addition to functioning as a retinol transporter, STRA6 is a cytokine signaling receptor.…”

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confidence: 87%

Reply to “How Free Retinol Behaves Differently from RBP-Bound Retinol in RBP Receptor-Mediated Vitamin A Uptake”

Noy

2014

Molecular and Cellular Biology

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Iacknowledge the letter of Zhong et al. (1). Our observations in references 2 to 5 demonstrated that, in addition to functioning as a retinol transporter, STRA6 is a cytokine signaling receptor. We showed that, upon activation by holo-RBP, STRA6 triggers a JAK/STAT cascade leading to induction of STAT target genes. As one such gene is the SOCS3 gene, a negative regulator of the insulin receptor, activation of STRA6 leads to insulin resistance. We showed further that the contribution of STRA6 to retinol uptake by mouse tissues in vivo is modest, except in the eye, and that the receptor is not necessary for maintaining vitamin A homeostasis either during embryonic development or in adults (6).Zhong et al.'s statement that these observations contradict "many studies" misrepresents the literature. Their cited reference 3 reported on experiments in zebrafish, their cited references 4 to 8 studied only STRA6-mediated transport, their cited reference 10 only characterized the effects of ablation of STRA6 on the eye, and their cited references 2 and 14 did not study STRA6 at all. Curiously, Dr. Sun is an author of a recent publication (7) that, while failing to cite our previously published observations (6), corroborates our findings that ablation of STRA6 does not generally impair retinoid status in mice.To Zhong et al. note that work from the Blaner laboratory demonstrated that RBP is critical for embryonic development under vitamin A-deficient conditions, attesting to the importance of RBP in supplying vitamin A to extrahepatic tissues (9). The observations that STRA6-null mice develop normally even under vitamin A deficiency (6) demonstrate that, unlike RBP, STRA6 is not critical for maintaining vitamin A homeostasis during development.Retinol can enter cells from extracellular holo-RBP either by free diffusion through the plasma membrane (reviewed in reference 10) or by STRA6-mediated transport. Zhong et al.'s observations that retinol can be readily taken up from the complex of holo-RBP with its binding partner in blood, TTR, simply reflect our findings that TTR does not interfere with uptake by diffusion (2, 11). In contrast, TTR competes with STRA6 for binding holo-RBP and thus blocks both retinol transport and cell signaling by the receptor (2

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How Free Retinol Behaves Differently from RBP-Bound Retinol in RBP Receptor-Mediated Vitamin A Uptake

Cited by 10 publications

References 23 publications

Spermatogenesis: The Commitment to Meiosis

Spermatogenesis: The Commitment to Meiosis

Biological Functions of RBP4 and Its Relevance for Human Diseases

Reply to “How Free Retinol Behaves Differently from RBP-Bound Retinol in RBP Receptor-Mediated Vitamin A Uptake”

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