Kinetic characteristics and mechanisms of regulation of receptor-dependent and receptor-independent LDL transport in the liver of different animal species and humans

In the normal animal and in humans, low-density lipoproteins (LDL) are removed from the plasma by both receptor-dependent and receptor-independent transport mechanisms. Most of the receptor-dependent transport activity is found in the liver, whereas the receptor-independent transport process is widely distributed in many organs. In the steady state the plasma LDL-cholesterol concentration is determined by the rate of LDL production, relative to the rate of LDL removal from the vascular space. This rate of removal in turn is determined by three transport parameters: J^m, the maximal transport rate for the receptor-dependent process in the whole animal; K_m, the concentration of LDL-cholesterol in the plasma at which half J^m is achieved; and P, the proportionality constant for the receptor-independent transport process. The values of these parameters are now known for several species, including humans and provide the basis for understanding how the plasma LDL-cholesterol concentration is altered by environmental factors such as aging and diet. With aging, for example, there appears to be no change in the receptor-dependent transport process, and in those situations in which the plasma LDL-cholesterol level rises, this increase appears to be caused by overproduction of LDL. With cholesterol feeding the plasma LDL-cholesterol level rises because of an increase in the LDL production rate coupled with a decrease in the maximal transport rate for the receptor-dependent process. The addition of saturated triglycerides to the diet further suppresses the J^m value, whereas unsaturated lipids enhance the maximal transport rate for LDL and lowers the plasma LDL-cholesterol level. Thus with these transport data it is now possible to identify the mechanism whereby any dietary or pharmacologic manipulation alters plasma LDL-cholesterol concentrations.