Female New Zealand White rabbits were fed either rabbit chow or rabbit chow plus 1% (w/w) cholesterol for 14 days. The chow-fed rabbits had normal plasma lipoprotein profiles on agarose gel electrophoresis, 59 +/- 5 mg of cholesterol and 5.5 +/- 0.4 mg of apolipoprotein E (apoE) per dl of serum. The cholesterol-fed rabbits had significant amounts of beta-VLDL in their serum, 1870 +/- 140 mg of cholesterol and 96 +/- 12 mg of apoE per dl of serum. Relative rates of apoE synthesis were determined by incubating hepatocytes in culture medium containing [3H]leucine for 15 min at 37 degrees C and expressing the radioactivity incorporated into immunoprecipitable apoE as a percentage of the radioactivity incorporated into total protein. Hepatocytes from cholesterol-fed rabbits had twice the relative rate of apoE synthesis (1.05 +/- 0.18%) of hepatocytes from chow-fed rabbits (0.55 +/- 0.07%). This increase in synthesis could be a major contributor to the 17-fold increase in serum apoE levels in the cholesterol-fed rabbit.