Discovery of LDL and the Birth of Lipidology

Lipids, such as cholesterol, its ester, and triglycerides, are insoluble in water and are transported in plasma and blood as emulsions. Their solubility is made possible by combining with phospholipids and proteins called apolipoproteins to form stable emulsified macromolecules. Lipoproteins were first described by Machboef, a Frenchman, in 1928 in his doctoral thesis.

They were subsequently classified based on their flotation rates in the ultracentrifuge or by their migration on electrophoresis. The very-low-density lipoproteins (VLDL) are secreted by the liver and converted to intermediate lipoproteins and then low-density lipoproteins (LDLs) in the circulation. The HDLs are also secreted by the liver while chylomicrons are secreted by the intestine.

In the early 1950s, Dr. John Gofman from the University of California at Berkeley used ultracentrifugation to separate plasma lipoproteins and described an association of increased CHD risk with elevations of LDL and decreased risk with elevations of HDL. The Framingham Heart Study from Framingham, Massachusetts, confirmed these findings through epidemiologic studies.

The Framingham investigators referred to elevated cholesterol (LDL-C), hypertension, and cigarette smoking as 3 major risk factors for CHD. Diabetes was subsequently added to this list. Controlling plasma cholesterol with diet and/or drugs became a national priority. In 1965 or 66, Fredrickson, Levy, and Lees published a series of landmark papers in the NEJM in which they proposed a system of classification of the lipoprotein disorders based on which lipids and lipoprotein families were elevated.

They used the Roman Numerals I through V to classify the disorders. Fredrickson et al. used electrophoresis on albuminated paper strips for qualitative assessment, ultracentrifugation, called beta quantification, to measure LDL-C and heparin precipitation to quantify HDL-C. Subsequently, Friedewald collaborated with Fredrickson and Levy to develop a simplified equation to quantify LDL-C.

A national diet-heart study was proposed and was deemed to be too expensive, and attention was given to drugs. Rudolf Altschul showed that nicotinic acid, or niacin, reduced cholesterol in the mid-1950s. At this time, it was the only drug available that lowered the levels of both cholesterol and triglyceride in blood. However, large gram quantities were required in order to reduce cholesterol and LDL. Triglycerides were reduced by about 30%, LDL by 15%-20%, while HDL was increased by 20%-25%. In the Coronary Drug Project, nicotinic acid reduced non-fatal cardiovascular events but failed to decrease total mortality, the primary endpoint. However, long-term follow-up showed a decrease in total mortality in the nicotinic acid group. Despite these positive results, the use of niacin was limited by flushing in most patients using this drug.