Discovery of the lipoproteins, their role in fat transport and their significance as risk factors.

The idea of a fat transport system in the plasma of mammals evolved slowly over three centuries. At the turn of this century, it was discovered that plasma globulins contained lecithin and that the digestion of plasma proteins with pepsin liberated small amounts of fat and cholesterol. The high density lipoprotein (HDL) was first isolated from horse serum in 1929 and the low density lipoprotein (LDL) in 1950. It was then shown that flotation of plasma in the ultracentrifuge revealed an array of lipoproteins that included VLDL, LDL and HDL and permitted quantitation. Subsequently, it was discovered that the free fatty acids (FFA) in plasma were bound to albumin and varied with feeding and fasting. From further studies, it was concluded that lipoprotein-bound triglycerides were delivered to adipose cells for uptake after meals; during fasting, the fat cells secreted FFA, which provided fuel for many tissues. The protein components of the lipoproteins (apopeptides) were characterized in the period from 1960 to 1970 and the LDL-receptor was identified in 1974. Fat transport was then established as a receptor-mediated delivery system of lipoproteins to targeted tissues. Defects in this system due to genetically altered or absent receptors explained dyslipidemias, which promoted atherosclerosis, xanthomatosis and Alzheimer's disease.