| Published: June 30, 2010. By Massachusetts General Hospital http://www.mgh.harvard.edu  |
Massachusetts General Hospital (MGH) investigators have found that an
enzyme with several important roles in energy metabolism also helps to
turn off the body's generation of fats and cholesterol under conditions
of fasting. The report in Genes & Development describes how
SIRT1, one of a group of enzymes called sirtuins, suppresses the
activity of a family of proteins called SREBPs, which control the body's
synthesis and handling of fats and cholesterol. The findings could lead
to new approaches to treating conditions involving elevated cholesterol
and lipid levels.
"SIRT1 had previously been shown to act as an energy sensor,
promoting the use of stored fat in response to food deprivation;
however, its function in shutting down fat and cholesterol synthesis was
unknown," says Amy Walker, PhD, of the MGH Cancer Center, the study's
lead author. "These findings point to SIRT1 as a master regulator of
physiologic energy stability that controls the synthesis and storage of
fat, as well as its usage as fuel."
Under normal conditions, the body produces appropriate levels of fats
and cholesterol, both of which are essential to life. A high-fat diet
can cause abnormal elevations in fat and cholesterol levels in the
blood, which may lead to cardiovascular disease, type 2 diabetes,
hypertension and other serious disorders. If the body is deprived of
food for a short time, it shuts down the production and storage of fat
and cholesterol and shifts to using stored fats as the primary source of
energy. Fasting also is known to turn off the activity of SREBP
proteins, and the research team investigated whether direct suppression
of SREBPs by SIRT1 was responsible for the metabolic shift.
A series of experiments in worms, fruitflies and mice showed that the
versions of SIRT1 present in those animals suppressed SREBP activity
and the associated synthesis and storage of fats. They also showed in
mouse and human cells that SIRT1 acts on SREBP by removing a protective
molecule, marking the protein for degradation, and that inhibiting SIRT1
activity caused levels of SREBP to rise. Treating genetically obese
mice fed a high-fat diet with an agent that increases sirtuin activity
suppressed the expression of SREBP-regulated fat synthesis genes and
also reduced the amount of fat stored in the animals livers.
"This study is significant because it explains the signals that tell
the body to burn fat in response to fasting or dieting," says David
Sinclair, PhD, a professor of Pathology at Harvard Medical School (HMS)
who helped discover the genes that code for sirtuins but was not
involved with this MGH-led study. "This improved understanding could
help treat and prevent metabolic diseases such as atherosclerosis and
type 2 diabetes."
Sirtuins have also been associated with the increased longevity in
response to reduced calorie intake observed in several species of
animals. Drugs that stimulate sirtuin activity are currently being
investigated for treatment of diabetes and related conditions.
"Sirtuin activators could strengthen SIRT1 functions that may be
suppressed in individuals with cardiometabolic disorders," explains
Anders Näär, PhD, of the MGH Center for Cancer Research, senior author
of the current study. "Our results suggest these agents may be able to
'trick' the body into responding as though it was experiencing fasting,
with beneficial metabolic consequences, but that hypothesis needs to be
tested in future studies." Näär is an associate professor of Cell
Biology and Walker is an instructor in Medicine at HMS.
