Title: Biochemical Basis for Depressed Serum Retinol Levels in Transthyretin-deficient Mice
Abstract: Transthyretin (TTR) acts physiologically in the transport of retinol in the circulation. We previously reported the generation and partial characterization of TTR-deficient (TTR<sup>−</sup>) mice. TTR<sup>−</sup> 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<sup>−</sup> mice accumulated RBP in their media to an identical degree, suggesting that RBP was being secreted from the hepatocytes at the same rate. <i>In vivo</i>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<sup>−</sup> mice at nearly identical rates. However, human retinol-RBP injected intravenously was more rapidly cleared from the circulation (<i>t</i><mml:math><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:math> = 0.5 h for TTR<sup>−</sup> <i>versus t</i><mml:math><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:math> >6 h for WT) and accumulated faster in the kidneys of TTR<sup>−</sup> 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<sup>−</sup> mice arise from increased renal filtration of the retinol-RBP complex.