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 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 Johns Hopkins team found that in these yeasts, 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," said
Peter J. Espenshade, a physiologist in the
Department of Cell Biology and a
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
PrizeÐwinning research by Michael S. Brown
and Joseph L. Goldstein, both of the Department of
Molecular Genetics, University of TexasÐ
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, cells happily go about
their business of manufacturing cholesterol in just the
right amounts, as determined by their Insig-
regulated sensors, Espenshade said.
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
said.
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, of Vanderbilt
University; David W. Powell, of the
University of Louisville; and John S. Burg, Raymond Chai,
Adam L. Hughes and Espenshade, all of Johns
Hopkins.