Fasting helps cause an enzyme with several important roles in energy metabolism to turn off the body’s generation of fats and cholesterol, Harvard researchers at Massachusetts General Hospital have found.  The findings could lead to new approaches to treating elevated cholesterol and lipid levels.

The researchers’ report, published today 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 study’s lead author is Amy Walker, PhD, of MGH’s Cancer Center, and an instructor at Harvard Medical School.  The senior author is Anders Näär,
PhD, assistant cell biologist at the MGH Center for Cancer Research,
and an associate professor of cell biology at the Harvard Medical School.

“This study is significant because it explains the signals that tell
the body to burn fat in response to fasting or dieting,” says David A. 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.”

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. 

Explains Walker, “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.  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.”

Fasting can 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.  The experiments 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 reduced the amount of fat stored in the animals livers.

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 treating diabetes and related conditions.  

“Sirtuin activators could strengthen SIRT1 functions that may be suppressed in individuals with cardiometabolic disorders,” explains Naar. “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.” 

The study was supported by the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at HMS and grants from the National Institutes of Health.  Additional co-authors of the Genes & Development article are Fajun Yang, Karen Jiang, Jun-Yuan Ji, Toshi Shioda, Peter Mulligan, Hani Najafi-Shoushtari, Josh Black, Jitendra Thakur, Johnathan R Whetstine, Raul Mostoslavsky and Nicholas Dyson, MGH Cancer Center; Jennifer Watts, Washington State University; Aparna Purushotham and Xiaoling Li, National Institute of Environmental Health Sciences; Olivier Boss, Michael Hirsch, Scott Ribich, Jesse Smith, Kristine Israelian and Christoph Westphal, Sirtris Pharmaceuticals; Joseph Rodgers and Pere Puigserver, Dana-Farber Cancer Institute, Sarah Elson and Lisa Kadyk, Exelixis, Inc., and Anne Hart, Brown University.