For some time scientists have believed that cholesterol plays a major role in heart disease because people with familial hypercholesterolemia, a genetic defect, have six to eight times the normal level of cholesterol in their blood. These people lack cell-surface receptors for LDL, which are the fundamental carriers of blood cholesterol to the body cells that use cholesterol. Without an adequate number of cell-surface receptors to remove LDL from the blood, the cholesterol-carrying LDL remain in the blood, increasing blood cholesterol levels. Scientists also noticed that people with familial hypercholesterolemia appear to produce more LDL than normal individuals. How, scientists wondered, could a genetic mutation that causes a slow-down in the removal of LDL from the blood also result in an increase in the synthesis of this cholesterol-carrying protein? Yoshio Watanabe of Kobe University in Japan in 1980 succeeded in breeding rabbits that had very high cholesterol levels. These rabbits spontaneously developed heart disease. The rabbits, like humans with familial hypercholesterolemia, lacked LDL receptors. Thus, scientists could study these Watanabe rabbits to gain a better understanding of familial hypercholesterolemia in humans. Before this, it was known that LDL are secreted from the liver in the form of a precursor, called VLDL, which carry triglycerides as well as relatively small amounts of cholesterol. The triglycerides are removed from the VLDL by fatty tissues. What remains is a remnant particle that must be removed from the blood. What scientists learned by studying the Watanabe rabbits is that the removal of the VLDL remnant requires the LDL receptor. Normally, the majority of the VLDL remnants go to the liver where they bind to LDL receptors and are degraded. In the Watanabe rabbit, due to a lack of LDL receptors on liver cells, the VLDL remnants remain in the blood and are eventually converted to LDL. The LDL receptors thus have a dual effect in controlling LDL levels. They are necessary to prevent oversynthesis of LDL from VLDL remnants and they are necessary for the normal removal of LDL from the blood. With this knowledge, scientists are now well on the way toward developing drugs that dramatically lower cholesterol levels in people afflicted with certain forms of familial hypercholesterolemia.