A hundred year history of cholesterol
May 01, 2015 -
Winners
of the Nobel Prize in 1985, Professors Joseph Goldstein (seated) and
Michael Brown (standing) of the University of Texas recently wrote a
brief history of cholesterol and heart disease over the previous century
in Cell – with a highly justified focus on their own groundbreaking
research contribution.
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."
Based on:
Goldstein JL & Brown MS, A Century of Cholesterol and Coronaries:
From Plaques to Genes and Statins, Cell 161, March 26, 2015
Last updated: 01.05.2015
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