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 characteriz ation of TTR-deficient (TTR-) mice. TTR- mice have very low circulating lev els of retinol and its specific transport protein, retinol-binding protein (RBP). We have examined the biochemical basis for the low plasma retinol-RB P levels. Cultured primary hepatocytes isolated from wild type (WT) and TTR - mice accumulated REP in their media to an identical degree, suggesting th at REP was being secreted from the hepatocytes at the same rate, In vivo ex periments support; this conclusion. For the first 11 h after complete nephr ectomy, the levels retinol and REP rose in the circulations of WT and TTR- mice at nearly identical rates. However, human retinol-RBP injected intrave nously was more rapidly cleared from the circulation (t(1/2) = 0.5 h for TT R- 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 comple x from the circulation to tissue interstitial fluids was identical in both strains. Taken together, these data indicate that low circulating retinol-R BP levels in TTRmice arise from increased renal filtration of the retinol-R BP complex.