Now, keep up to date
with daily feeds of newly posted stories
about America's Seniors...click on the box
to the left
Clues about Controlling Cholesterol rise
from Yeast studies
Newswise — Having discovered how a lowly,
single-celled fungus regulates its version
of cholesterol, Johns Hopkins researchers
are gaining new insight about the target and
action of cholesterol-lowering drugs taken
daily by millions of people to stave off
heart attacks and strokes. Their work
appears in the December issue of Cell
Metabolism.
In humans, statin drugs inhibit an enzyme,
HMG-CoA reductase, to lower blood
cholesterol. What’s not as well understood
are the multiple layers of control for the
enzyme, especially the regulatory protein
Insig.
Because components of the
cholesterol-regulatory system have been
conserved across 400 million years of
evolution, a yeast called fission yeast is a
good model for delving fast and deep into
molecular details of how mammalian cells
regulate HMG-CoA reductase.
The Hopkins team found that in these yeast,
so named because they divide in the middle,
Insig also regulates HMG-CoA reductase but
does it differently. In mammals, Insig
degrades this enzyme — essentially
destroying it — while in fission yeast,
Insig inactivates the enzyme simply by
promoting the attachment of a phosphate.
“This is a surprising fundamental
difference,” says Peter J. Espenshade, a
physiologist in the Department of Cell
Biology and member of the Center for
Metabolism and Obesity Research at the Johns
Hopkins University School of Medicine.
Despite a decidedly bad rep, cholesterol has
good purpose — in the right amounts and in
the right places — as the raw material for
the production of steroid hormones and bile
acids. Cholesterol also sits in the
membranes of cells, maintaining the barrier
between them and their environment. But the
thing that makes it most useful in cell
function — its absolute inability to
dissolve in water — also makes it lethal.
When cholesterol accumulates in the wrong
place — say, within the wall of an artery —
it leads to plaque formation and
atherosclerosis.
The Johns Hopkins team’s seek-and-find
mission for new parts of the molecular
machine that regulates the manufacture of
cholesterol builds on Nobel-prize winning
research by Michael S. Brown and Joseph L.
Goldstein of the Department of Molecular
Genetics, University of Texas - Southwestern
Medical School, who discovered that cells of
the human body have receptors on their
surfaces that trap and absorb bloodstream
particles containing cholesterol.
Using fission yeast, the Johns Hopkins
scientists identified the protein Insig as
an integral part of the sensor system in
cells that measures cholesterol levels. When
all is well with cells, they happily go
about their business of manufacturing
cholesterol in just the right amounts, as
determined by their Insig-regulated sensors,
Espenshade says.
As in humans, Insig in yeast limits
cholesterol production by inactivating the
enzyme HMG-CoA reductase. How the yeast
stopped synthesizing cholesterol was what
surprised the scientists, however.
Stressed fission yeast activated a protein
called MAPK which, partnering with the
protein Insig, attaches a phosphate onto the
enzyme HMG-CoA reductase by a process known
as phosphorylation and shuts down
cholesterol manufacture. These findings
explain how a cell can change cholesterol
production in response to a stressful
environment.
“In this study, we not only learned
something new about how Insig works and
cholesterol biology, but we also found a
rare example of a MAPK controlling a
biosynthetic enzyme,” Espenshade says.
By studying Insig control of HMG-CoA
reductase in yeast, the researchers hope to
inform improvements to the efficacy of
statin and other cholesterol-lowering
therapies.
The research was supported by the National
Institutes of Health.
Authors on the paper are Andrew J. Link,
Vanderbilt University School of Medicine;
David W. Powell, University of Louisville
School of Medicine; and John S. Burg,
Raymond Chai, Adam L. Hughes and Espenshade,
all of Hopkins.
... ..
...
...