A Comparison of the Uptake, Metabolism and Biologic Effects of Retinol Delivered to Human Keratinocytes Either Free or Bound to Serum Retinol-Binding Protein

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In response to body demands, retinol (ROL) is secreted from the liver into the circulation bound to serum retinol-binding protein (RBP). The mechanism by which ROL is transferred from RBP to target cells remains controversial. To study ROL delivery, we have used a model system of cultured human foreskin keratinocytes (HKc) to compare the uptake, metabolism and biologic effects of ROL added either directly to the medium or bound to RBP. [3H]ROL added directly to the medium was rapidly taken up by HKc, and maximal accumulation of [3H]ROL occurred by 3 h. In contrast, [3H]ROL delivered bound to RBP was taken up very slowly but at a linear rate for at least 72 h. Several experimental approaches indicated that ROL uptake from RBP was not mediated by a cell surface receptor for RBP. The rate and extent of [3H]ROL metabolism to retinyl esters was the same whether the ROL was added directly to the medium or bound to RBP. In addition, several biologic responses by HKc to ROL showed the same dose response curves whether the ROL was added directly to the medium or bound to RBP. Overall, the results support a model of ROL uptake from RBP in which the vitamin is first slowly released from RBP into the aqueous phase and then becomes cell associated. In this manner, the cells are provided with a slow but constant supply of ROL and are protected from the rapid and potentially toxic accumulation of ROL that occurs in the absence of RBP.