Down-regulation of hepatic LDL receptor protein and messenger RNA in fasted rabbits

Rabbits fasted for 9 and 14 d exhibited 6- and 8-fold increase in plasma cholesterol level, respectively. As one of the mechanisms causing hypercholesterolemia in fasted rabbits, the decreased activity of hepatic low-density lipoproteins (LDL) receptor has been reported (Stoudemire, J.B., Renaud, G., Shames, D.M., & Havel, R.J. (1984) J. Lipid Res. 25, 33-39). In order to demonstrate the down-regulation of hepatic LDL receptor on a molecular basis, we carried out immunoblotting of the liver membranes with a specific antibody against LDL receptors and blot hybridization of hepatic RNAs with cDNA of LDL receptor. Immunoblotting showed that LDL receptors in fasted rabbits were markedly decreased, and blot hybridization of RNAs showed a significant decrease in mRNA level of hepatic LDL receptor in fasted rabbits. Further, significant decreases both in LDL binding to liver membrane and in hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in fasted rabbits were demonstrated. From these results, we concluded that hypercholesterolemia in fasted rabbits is caused by the impaired catabolism of LDL due to down-regulated biosynthesis of hepatic LDL receptor.