STUDIES ON THE METABOLISM OF RETINOL AND RETINOL-BINDING PROTEIN IN TRANSTHYRETIN-DEFICIENT MICE PRODUCED BY HOMOLOGOUS RECOMBINATION

Tissue needs for retinoids are believed to be satisfied through the de livery in the circulation of retinol by its specific plasma transport protein, retinol-binding protein (REP), which circulates as a 1-to-1 p rotein complex with transthyretin (TTR). The binding of REP to TTR is thought to prevent filtration of retinol-RBP in the kidney and to play a role in secretion of REP from hepatocytes. Recently a strain of mic e (TTR(-)) that totally lacks immunoreactive TTR was produced by targe ted mutagenesis. We have explored the effects of TTR deficiency on ret inol and REP metabolism in this mutant strain. In pooled plasma from t he TTR(-) mice retinol levels averaged 6% of those of wild type animal s. Similarly, plasma REP in the TTR(-) mice was found to be 5% of wild type levels. Hepatic retinol and retinyl ester levels were similar fo r mutant and wild type mice, suggesting that the mutation affects neit her the uptake nor storage of dietary retinol. Levels of retinol and r etinyl esters in testis, kidney, spleen, and eye cups from TTR(-) mice were normal. Plasma all-trans-retinoic acid levels for the TTR(-) mic e were 2.3-fold higher than those of wild type (425 versus 190 ng/dl). Kidney REP levels were similar for the mutant and wild type mice and we were unable to detect intact REP in urine from TTR(-) mice. Hepatic REP levels in the TTR(-) mice were 60% higher than those of wild type mice (39.8 versus 25.0 pp of RBP/g of tissue). These data may suggest that there is a partial blockage in REP secretion from TTR(-) hepatoc ytes that leads to lessened plasma levels of retinol-RBP.