Statins: Definitive Translational Research

The development of cholesterollowering statins is one of the highlights of transitional medicine. Statins reduce serum low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins. Statin use in clinical practice is the outgrowth of extensive research into cholesterol and lipoprotein metabolism, drug discovery and randomized clinical trials (RCTs). Each of these areas is worthy of some review. Cholesterol was first discovered in gallstones. It was named cholesterine by the French chemist Chevreul in 1816. In 1856, Virchow found that lipid (cholesterol) is a key component of atherosclerotic plaques. Subsequently, 13 Nobel Prizes have been awarded to scientists who have studied the structure, chemistry, biochemistry and biology of cholesterol. It has been known for 100 years that high serum cholesterol produces atherosclerosis in animals (1). In the 1940s and 1950s, it was observed that high serum cholesterol consistently associates with premature atherosclerotic disease in humans. Shortly thereafter, cholesterol was discovered to be carried in lipid-protein complexes called lipoproteins (2). Among the lipoproteins, LDL is the predominant atherogenic lipoprotein. LDL from the blood filters into the arterial wall and starts the process of atherogenesis (3). All of the steps whereby LDL initiates atherogenesis and produces cholesterol-rich atherosclerotic plaques are still not fully understood. But importantly, in some individuals, a plaque becomes unstable and undergoes rupture. When this occurs, arterial thrombosis follows and precipitates an acute cardiovascular event (4). Coronary thrombosis and stroke are the major killers accompanying atherosclerosis. The zenith of cholesterol research was the discovery of the LDL receptor by Michael Brown and Joseph Goldstein (5). LDL receptors are located mainly on the surface of liver cells. They recognize the protein component of LDL, known as apolipoprotein B, and remove LDL from the circulation. In a word, LDL receptor expression regulates serum levels of LDL-C. Underexpression leads to hypercholesterolemia; overexpression reduces serum cholesterol levels. LDL receptors also remove some triglyceride-rich lipoproteins but mainly cholesterolenriched LDL. The discovery of the LDL receptor uncovered a potential pathway for markedly lowering levels of serum LDL and preventing atherosclerosis. The mechanisms underlying the regulation of LDL receptor expression have been worked out in exquisite detail by Brown, Goldstein and their colleagues (6). One consequence of the discovery of the LDL receptor was the uncovering of the cause of a condition called familial hypercholesterolemia (FH). In this condition, serum LDL-C levels are elevated from birth and remain elevated throughout life. High LDL-C levels cause the buildup of cholesterol in arteries leading to premature atherosclerotic cardiovascular disease (ASCVD). FH occurs in two forms: heterozygous and homozygous. The former confers half the normal number of LDL receptors; in the latter, receptors are absent. Heterozygous FH patients have twice the normal levels of LDL-C, whereas in homozygous FH levels, LDL-C concentrations are about four Statins: Definitive Translational Research