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Originally published In Press as doi:10.1074/jbc.M008091200 on October 17, 2000

J. Biol. Chem., Vol. 276, Issue 2, 1107-1113, January 12, 2001
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Biochemical Basis for Depressed Serum Retinol Levels in Transthyretin-deficient Mice*

Ariëtte M. van BennekumDagger , Shuanghong WeiDagger , Mary V. GambleDagger §, Silke Vogel§, Roseann Piantedosi§, Max Gottesman, Vasso Episkopou||, and William S. BlanerDagger §**

From the Dagger  Institute of Human Nutrition, the § Department of Medicine, and the  Institute of Cancer Research of the College of Physicians and Surgeons, Columbia University, New York, New York 10032 and the || Medical Research Council, Hammersmith Hospital, London W12 0NN, United Kingdom

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.


* This work was supported by Grants EY12858 and DK52444 from the National Institutes of Health and grants from the United States Department of Agriculture.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Medicine, Hammer Health Sciences Bldg., Rm. 502, Columbia University, 701 W. 168th St., New York, NY 10032. Tel.: 212-305-5429; Fax: 212-305-2801; E-mail: wsb2@columbia.edu.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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