Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice

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 REP in their media to an identical degree, suggesting that REP 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 REP 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 (t(1/2) = 0.5 h for TTR- versus t(1/2) > 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 TTRmice arise from increased renal filtration of the retinol-RBP complex.