In the 1970s, Joseph Goldstein and I discovered that the level of low density lipoprotein (LDL) in plasma is controlled by the number of LDL receptors on liver cells. We also found that the production of LDL receptors is regulated. When liver cells are deficient in cholesterol, the gene for the LDL receptor is activated, and large numbers of LDL receptors are produced. As a result, plasma LDL levels fall. One way to reduce liver cholesterol levels is to block cholesterol synthesis. The possibility of blocking synthesis was first realized in 1976 with the publication of a major discovery from Japan.
Akira Endo, a biochemist at the Sankyo drug company in Tokyo, screened many fungal extracts seeking for a molecule that would block cholesterol synthesis. He found a potent molecule which he called ML-236B. He showed that ML-236B is acompetitive inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate determining enzyme in the cholesterol biosynthetic pathway.
After Endo published his discovery, Dr. Goldstein and I collaborated with him to determine whether the block in cholesterol synthesis would lead to an increase in LDL receptors and a fall in plasma LDL. We showed this to be the case initially in cultured human fibroblasts and subsequently in dogs. ML-236B never reached the marketplace because the Sankyo company feared that it might cause cancer. This fear was not correct.
At this point, an American drug company, Merck, took up the challenge. They discovered a molecule called lovastatin that was closely related to ML-236B. They conducted clinical trials showing that lovastatin lowered plasma LDL levels. On the basis of this lowering, lovastatin was approved by the US FDA in 1987 and it reached the market as Mevacor, the first statin drug. This was shortly followed with several other statins isolated from other molds. Many clinical trials have shown that statins reduce plasma LDL-cholesterol levels. As a result, heart attacks are prevented, and life is extended. Currently, statin drugs are taken daily by more than 30 million people.
In recent years Dr. Goldstein and I discovered the mechanism by which statins raise LDL receptors. The key is a membrane-bound transcription factor called Sterol Regulatory Element Binding Protein (SREBP) that senses the level of cholesterol in cell membranes. Statins block cholesterol synthesis, which causes the level of cholesterol in cell membranes to fall. This releases SREBP from its position in endoplasmic reticulum membranes, allowing it to reach the nucleus. There it activates the LDL receptor gene, increasing LDL receptors and increasing the uptake of LDL-cholesterol. This restores cellular cholesterol levels and lowers the level of LDL in blood. Statin-mediated activation of SREBP has the potential to reduce dramatically deaths from heart attacks in Western countries.
