Retinol Binding Protein and Transthyretin Are Secreted as a Complex Formed in the Endoplasmic Reticulum in HepG2 Human Hepatocarcinoma Cells

Bellovino, Diana; Morimoto, Takashi; Tosetti, Francesca; Gaetani, S.

doi:10.1006/excr.1996.0010

Cited by 66 publications

(50 citation statements)

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“…Whether TTR deficiency inhibits RBP secretion or whether the accumulation of RBP exceeds the secretion capacity of the hepatocyte remains to be determined. However, the accumulation of intracellular RBP in TTR-deficient hepatocytes is entirely consistent with observations that TTR facilitates RBP synthesis and/or secretion from HeLa cells (21,22) and from human HepG2 hepatoma cells (23).…”

Section: Resultssupporting

confidence: 88%

“…This hypothesis, although reasonable, had not been verified experimentally. TTR was also suggested to facilitate RBP synthesis/secretion from liver (21)(22)(23). Studies with 4-hydroxy-N-phenylretinamide, which disrupts the RBP-TTR complex and markedly lowers circulating retinol-RBP levels, suggested that unbound circulating RBP infiltrates into the interstitial space within tissues (24).…”

Section: Resultsmentioning

confidence: 99%

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Biochemical Basis for Depressed Serum Retinol Levels in Transthyretin-deficient Mice

Bennekum¹,

Wei²,

Gamble³

et al. 2001

Journal of Biological Chemistry

107

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Transthyretin (TTR) acts physiologically in the transport of retinol in the circulation. We previously reported the generation and partial characterization of TTR-deficient (TTR ؊ ) mice. TTR ؊ mice have very low circulating levels of retinol and its specific transport protein, retinol-binding protein (RBP). We have examined the biochemical basis for the low plasma retinol-RBP levels. Cultured primary hepatocytes isolated from wild type (WT) and TTR ؊ mice accumulated RBP in their media to an identical degree, suggesting that RBP was being secreted from the hepatocytes at the same rate. In vivo experiments support this conclusion. For the first 11 h after complete nephrectomy, the levels retinol and RBP rose in the circulations of WT and TTR ؊ mice at nearly identical rates. However, human retinol-RBP injected intravenously was more rapidly cleared from the circulation (t1 ⁄2 ‫؍‬ 0.5 h for TTR ؊ versus t1 ⁄2 >6 h for WT) and accumulated faster in the kidneys of TTR ؊ compared with WT mice. The rate of infiltration of the retinol-RBP complex from the circulation to tissue interstitial fluids was identical in both strains. Taken together, these data indicate that low circulating retinol-RBP levels in TTR ؊ mice arise from increased renal filtration of the retinol-RBP complex.The predominant retinoid in the fasting circulation is retinol (1, 2). All circulating retinol is bound to its specific plasma transport protein, the 21-kDa retinol-binding protein (RBP) 1 (1, 2). RBP, which is synthesized and secreted primarily by hepatocytes, is the sole specific transport protein for retinol in the circulation (1, 2). The secretion of RBP is strongly stimulated by its association with retinol, which alters the conformation of the protein (1, 2). In blood, RBP is found as a 1:1 protein-protein complex with a 55-kDa serum protein, transthyretin (TTR) (1, 2). Association with TTR is proposed both to facilitate RBP release from its site of synthesis in the endoplasmic reticulum (2) and to prevent renal filtration of RBP (1). Delivery of retinol to cells through the circulation by the RBP-TTR complex is the major pathway through which cells and tissues acquire retinol. It is generally accepted that cells and tissues acquire the retinoic acid they need for regulating gene expression via intracellular oxidation of this retinol to retinoic acid (3).We previously reported the targeted disruption of the mouse gene for TTR (4, 5). Although TTR-deficient (TTR Ϫ ) mice have no immunoreactive TTR, they appear normal and are viable and fertile (4). Yet, these mutant mice show marked biochemical differences when compared with wild type (WT) mice in parameters associated with retinoid transport and metabolism (4, 5). The plasma retinol and RBP levels in TTR Ϫ mice are very low, ϳ5% of those observed in WT mice (4, 5). These retinol levels correspond to those seen in severely vitamin A-deficient animals that are near death (4, 5). Nevertheless, despite these low circulating levels of retinol-RBP, total retinol (retinol ϩ retinyl ester) level...

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Biochemical Basis for Depressed Serum Retinol Levels in Transthyretin-deficient Mice

Bennekum¹,

Wei²,

Gamble³

et al. 2001

Journal of Biological Chemistry

107

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“…Retinoids comprise a group of structural and functional analogs of vitamin A. RBP is the specific carrier of retinol in the blood and transports it from the liver to the target tissues. Interaction between RBP and TTR in hepatocytes before their secretion into the bloodstream has already been described by Bellovino et al (24). We have demonstrated an interaction between TTR and RBP-4.…”

Section: A B Csupporting

confidence: 83%

Confirmation of the biological significance of transthyretin as a biomarker for cutaneous T-cell lymphoma by its protein interaction partners

Eggeling¹

2010

Mol Med Rep

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Abstract. We previously identified transthyretin (TTR) and its posttranslational modifications as a down-regulated marker in mycosis fungoides (MF), a benign subtype of cutaneous T-cell lymphoma (CTCL). In order to more precisely understand the biological role of TTR in the etiology of MF, it is essential to clarify the pathways of progression by identifying further interacting proteins. This study is the first to combine blue native polyacrylamide gel electrophoresis (BN-PAGE) with surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to detect new TTR interaction partners and to determine whether these TTR interaction partners can themselves be used as biomarkers. By this procedure, apolipoprotein A1, which was additionally found to be down-regulated in the serum of MF patients, apolipoprotein A4, retinol binding protein 4 (RBP-4), and retinoid X receptor β (RXR-β) were identified as interaction partners of TTR. The RXR family plays a role in cell differentiation and proliferation and is known to be the target of bexarotene, which is used in the treatment of CTCL. In conclusion, the combination of BN-PAGE and SELDI-TOF-MS used in this study allowed for the detection of protein interaction partners, which, in the case of RBP-4 and RXR, indicated a connection between the common tumor marker TTR and tumor progression in CTCL.

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“…In mammals, retinol is the major circulating retinoid. Retinol is typically bound to retinol-binding protein 4 (RBP4) and transthyretin (TTR), and taken up by target tissues (10). Previous studies demonstrated that retinol-RBP-TTR complex (holo-RBP) uptake was facilitated by STRA6 (stimulated by retinoic acid gene 6) in various tissues (93).…”

Section: Vitamin a Metabolism And Ra Synthesismentioning

confidence: 99%

“…Some studies have revealed the role of RA in maintaining the immune tolerant microenvironment in the eye through inhibition of Th1/Th17 response and promotion of Treg development. Immunization of C57BL/6 mice with human interphotoreceptor retinoid binding protein peptide 1 to 20 [IRBP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) ] elicited experimental autoimmune uveoretinitis (EAU). Keino et al (95) reported that intraperitoneal RA administration dampened the severity of EAU when administrated at 200 g/mouse (ϳ20-fold above normal sera RA concentration, every other day) before the disease onset.…”

Section: Ra Regulates Uveitismentioning

confidence: 99%

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

Guo

Brown

Ortiz

et al. 2015

Physiological Reviews

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Although vitamin A was recognized as an "anti-infective vitamin" over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell-and humoralmediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases.

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Retinol Binding Protein and Transthyretin Are Secreted as a Complex Formed in the Endoplasmic Reticulum in HepG2 Human Hepatocarcinoma Cells

Cited by 66 publications

References 0 publications

Biochemical Basis for Depressed Serum Retinol Levels in Transthyretin-deficient Mice

Biochemical Basis for Depressed Serum Retinol Levels in Transthyretin-deficient Mice

Confirmation of the biological significance of transthyretin as a biomarker for cutaneous T-cell lymphoma by its protein interaction partners

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

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