Feedback inhibition of apolipoprotein A-I synthesis by its propeptide in hepatocyte cell culture and in the cell-free system

Addition of chemically synthesized proapolipoprotein A-I hexapeptides in a concentration of 10 -4 mol/l in the medium of primary rat hepatocyte cell cultures decreased net apolipoprotein A-I synthesis by up to 13%. The inhibition was dose dependent and slightly different for the three peptides with differing amino acid sequences. The synthesis of albumin remained unaltered. In a reticulocyte cell-free system the three propeptides, in a concentration of 10 -4 mol/l, inhibited apolipoprotein synthesis by 42%, 43%, and 48%, respectively. Total protein synthesis was inhibited by 19%, 22%, and 24 % only. All three propeptides in concentrations of 10 -7 to 10 -4 mol/l inhibited apo A-I synthesis in a dose dependent manner, indicating that the identical C-terminal sequence (Phe-Trp-Gln-Gln) is responsible for the inhibitory effect. The synthesis of albumin was not inhibited. The proalbumin hexapeptide (Arg-Gly-Val-Phe-Arg-Arg) at a concentration of 10 -3 mol/l inhibited albumin synthesis by 63% whereas incorporation into apoA-I was inhibited by only 14%. Amino acids in concentrations equimolar to the propeptides had no effect on the incorporation into total protein, apoA-I, and rat serum albumin. These results suggest that the synthesis of apolipoprotein A-I is regulated by a feedback mechanism with its propeptide as inhibitor.