A hundred year history of cholesterol

Joseph Goldstein, MD; Michael Brown, MD; University of Texas, Dallas, USA

"Today, around 25% of all deaths in industrialized countries can be attributed to coronary heart disease. It may come as some surprise that heart attacks were first recognized as a clinical condition as late as 100 years ago. In 1910, the German chemist, Adolf Windaus found the first hint that cholesterol tended to mass in atherosclerotic plaques. In 1938, Norwegian physician Carl Müller first described the hereditary condition familial hypercholesterolemia (FH) where the concomitant greatly increased blood cholesterol levels were associated a massive increase in a risk of heart attack in middle age. In 1955, John Gorman, a physician from the University of California, first separated blood lipoproteins from blood plasma into LDL and HDL. He then looked at the plasma of patients who had had heart attacks and consistently found significantly higher levels of LDL and lower levels of HDL.

On a population level, communities with low fat intakes also tend to have low cholesterol levels in their blood, but if they should move from that community to a region with high fat intake, then their plasma cholesterol levels will rise to a similar level as the locals. 

Cholesterol is indirectly synthesized from repeated polymerization of the simple acetate moiety. In 1964, the Nobel Prize was given to Konrad Bloch and Feodor Lynen who first found the metabolite 3-hydroxy-3 methyl glutarate attached to CoA (HMG CoA) which was dedicated to cholesterol synthesis. From this discovery, research concentrated on regulating the cholesterol synthesis rate controlling enzyme, HMG CoA reductase.

A LDL particle is spherical in shape with a phospholipid coating around a core filled with cholesterol ester molecules. A single protein, apoliprotein B (apoB), is bound to the phospholipid surface. One theory as to the role of LDL in plaque formation is that it partially penetrates the vascular epithelium. The exposed lipids are oxidized, which in turn modify the ApoB structure. The modified ApoB attracts the attention of wandering macrophages in the blood, which ingest the LDL and are then themselves converted to cholesterol-laden foam cells. The foam cells themselves secrete metabolites that result in severe local inflammation and the initiation of plaque formation.

In the late seventies, Goldstein and Brown were able to demonstrate how cells take up LDL. They found specific surface receptors in cells (clustered in coated pits) that bind with the apoB. The LDL is then admitted to the cell where cholesterol is released by the action of cholesterol esters. They also discovered a homeostatic feedback mechanism that meant increased cell cholesterol levels resulted in a reduction in the production of LDL receptors and the HMG CoA reductase. There is an important genetic component to density of LDL receptors in cells. The genes of sufferers of familial hypercholesterolemia (FH) result in a major reduction in the concentration of LDL receptors, hence the cells are much less able to process cholesterol with a resulting massive build-up of cholesterol in the blood plasma itself.

It was in 1976 that the Japanese company Sankyo first developed the class of cholesterol lowering pharmaceutical agents known as statins. They work by inhibiting the cellular production of HMG CoA reductase. However, it was not until 1987, that the first statin for human use was approved (Merck’s Mevacor). Whilst it was known that statin regulated the cells cholesterol feedback mechanism, it was not known how. This situation was resolved by Goldstein and Brown in the nineties. They found a key regulating substance called sterol regulatory element binding protein-1 (SBREP-1) and over the following years, elucidated its complex intracellular journey from the cell membrane to the nucleus.

The targeted application of therapies design to reduce LDL levels in blood has undoubtedly made a major contribution in treating and preventing heart disease. However, the decision on when to intervene remains complex and would be aided immeasurably if rapid, non-invasive methods could be developed that detect and monitor atherosclerotic plaques in the coronary arteries."