In the March 3 issue of Nature, Johns Hopkins
researchers report that two proteins best known for very
different activities actually come together to turn the
liver into a sugar-producing factory when food is scarce.
Because the liver's production of sugar is a damaging
problem in people with diabetes, the proteins' interaction
might be a target for future drugs to fight the disease,
the researchers say.
Under normal circumstances, the liver's production of
sugar is a backup plan that enables survival during food
shortages; the brain and certain other critical organs rely
on sugar — specifically glucose — for the
energy to function. In people with diabetes, however, the
liver doesn't sense the incoming calories, and it keeps
making glucose when it shouldn't.
The researchers discovered in fasting mice that the
liver's production of sugar kicked into high gear because
amounts and activities of the two proteins, called sirtuin1
and PGC1-alpha, increased when dietary calories weren't
available. Once mice were fed, levels of the two proteins
went down, and sugar production ceased.
"It isn't a coincidence," said Pere Puigserver, an
assistant professor of
cell biology at the School of
Medicine's Institute for Basic Biomedical Sciences. "The
two proteins actually bind to each other, and without
sirtuin1, PGC1 can't make glucose."
A current diabetes-fighting drug, metformin, blocks
steps in the glucose-making process, but the new research
identifies a critical regulatory step the researchers say
could be targeted as well.
PGC1, which Puigserver isolated and cloned in 1998 as
a postdoctoral fellow at Harvard, controls gene expression
in the liver and other tissues. In the liver, it triggers
the conversion of fats into sugar, particularly when access
to food is limited. But no one knew exactly how it was
controlled or what else it might need in order to launch
the sugar-making process.
Sirtuin1, like its sirtuin relatives, is best known
for removing molecular "decorations" on proteins that help
organize DNA and restrict access to genes. It turns out
that sirtuin1 also removes these decorations from PGC1 and
then remains bound to PGC1 as it starts up the sugar-making
process, the researchers found.
"Because both proteins are required for the liver to
make sugar, targeting sirtuin1 in a very specific way might
help control sugar production in people with diabetes,"
Puigserver said. "Sirtuin1 interacts with many different
proteins, and it's just this one interaction you would want
But, he said, PGC1 has an unusually close relationship
with sirtuin1 that may make for relatively easy picking.
PGC1, unlike the vast majority of proteins, only uses
sirtuin1 to remove its "decorations," called acetyl groups.
Most other proteins can have the groups plucked off by a
number of different enzymes.
"PGC1 is a 'clean' target for sirtuin1," Puigserver
said. "If sirtuin1 isn't available, PGC1 becomes covered in
acetyl groups, and the acetyl-covered PGC1 can't make
In the researchers' experiments, graduate student
Joseph Rodgers also discovered that the livers of fasted
mice first developed high levels of a chemical called
pyruvate, which is a starting material for making glucose,
and then accumulated high levels of sirtuin1 protein.
(Rodgers will receive the Nupur Dinesh Thekdi Research
Award on April 14 for this work as part of the School of
Medicine's 28th annual Young Investigators' Day
"When there's no incoming food, muscles make lactate
and alanine and send them to the liver to be converted into
pyruvate and glucose," Puigserver said. "It appears, from
our work, as though the pyruvate then triggers increased
production of sirtuin1, which in turn lets PGC1 start
converting the pyruvate into the glucose the body needs to
The relationship between sirtuin1 and PGC1 also
connects processes involved in cellular aging and
responding to calorie intake in mammals for the first time.
In bacteria and yeast, the equivalent of sirtuin1 is
already known to help slow processes linked to cellular
aging when food is scarce, an effect that extends the
single-celled organism's lifespan.
"We now know that sirtuin1 is directly involved in the
response to calorie restriction in mammals and in processes
involved in cellular aging," Puigserver said. "But we still
don't know whether sirtuin1's activity affects lifespan in
There is a precarious anecdotal link, however. In
2003, other scientists reported that a compound found in
red wine activated yeast's sirtuin1-equivalent and extended
the organism's lifespan. Moving up the food chain, decades
of reports have shown that drinking moderate amounts of red
wine is associated with a longer life for people.
But at this point, knowing for sure whether sirtuin1
helps extend lifespan (an organism issue) or is merely
involved in cellular aging (a cell-by-cell issue) in
mammals will take much more work. Sirtuin1's potential as a
target for treating diabetes is much closer, Puigserver
The researchers are now probing the pyruvate-sirtuin1
connection more closely and looking for more details of the
sirtuin1-PGC1 interaction. Also on the to-do list:
examining sirtuin1 and PGC1 in other tissues, particularly
muscle and fat, two other energy-producing tissues in
The study was funded by the Ellison Medical
Foundation, the American Federation for Aging Research and
start-up funds from the Department of Cell Biology at the
Johns Hopkins School of Medicine.
Authors on the paper are Rodgers, Puigserver and
Carlos Levin, all of Johns Hopkins; and Wilhelm Haas,
Steven Gygi and Bruce Spiegelman, of Harvard Medical