Modulation of the activity of the human cholesteryl ester transfer protein by carboxylated derivatives. Evidence for 13-cis-retinoic acid as a potent activator of the protein's activity in plasma.

The influence of palmitic acid, 13-cis-retinoic acid, all-trans-retinoic acid, and all-trans-retinol on the activity of the human cholesteryl ester transfer protein (CETP) was evaluated either in total human plasma supplemented with a tracer dose of 3H-labeled cholesteryl-ester-containing high-density lipoprotein sub-fraction 3 ([3H]CE-HDL3), or in reconstituted mixtures containing [3H]CE-HDL3, isolated low-density lipoproteins (LDL), and purified CETP. In reconstituted mixtures, all the carboxylated derivatives increased progressively and significantly the transfer of 3H-labeled cholesteryl esters from [3H]CE-HDL3 towards LDL in the 20-100 microM concentration range. Under identical experimental conditions, CETP activity was only minimally modified in the presence of all-trans-retinol. When present at a concentration of 60, 80, or 100 microM, 13-cis-retinoic acid was a significantly more potent activator of CETP activity than all the other derivatives studied (P < 0.01 in all cases). In contrast to observations made with reconstituted mixtures, only 13-cis-retinoic acid, but not palmitic acid, was able to induce a significant, concentration-dependent stimulation of CETP activity in total human plasma. In fact, differences in the ability of 13-cis-retinoic acid and palmitic acid to modulate the plasma cholesteryl ester transfer reaction were linked to their relative affinity for albumin and lipoprotein substrates: fatty-acid-poor albumin reduced CETP activity to a significantly greater extent in reconstituted mixtures containing palmitic acid than in reconstituted mixtures containing 13-cis-retinoic acid (P < 0.01 for all the incubation mixtures in the 1-10 g/l albumin concentration range); palmitic acid presented a markedly lower ability to increase the electrophoretic mobility of LDL and HDL fractions in total plasma than 13-cis-retinoic acid. In support of a key role of the negatively charged carboxylic group of 13-cis-retinoic acid in upregulating CETP activity, cholesteryl ester transfer rates correlated positively with the electrophoretic mobility of LDL (r = 0.98; P < 0.0002) and HDL (r = 0.96; P < 0.0008) in total plasma supplemented with the carboxylated compound. It is concluded that 13-cis-retinoic acid can upregulate the CETP-mediated cholesteryl ester transfer reaction both in reconstituted mixtures containing isolated lipoproteins and purified CETP, and in total normolipidemic human plasma.