SIRT3 Gene May Be Key To Understanding Metabolic Syndrome

New research shows that the SIRT3 gene may contribute to obesity as well as a variety of chronic diseases including diabetes, heart disease, and high blood pressure. The study was published in the August 18th issue of Molecular Cell.

The scientists studied laboratory mice to better understand the relationship between major mitochondrial protein deacetylase SIRT3 and metabolic syndrome. After placing the mice on a high-fat diet, the researchers found that mice that lacked the SIRT3 gene showed accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type mice. In addition, the researchers found that prolonged high-fat diets in normal mice reduced the activity of the enzyme produced by SIRT3. This reduced enzyme activity can lead to a build-up of fat in the bloodstream and liver, which in turn can lead to obesity, high blood pressure, and insulin resistance. Normally, SIRT3 initiates a chain reaction that allows for the transformation of fat into energy at the cellular level.

The researchers also looked at the SIRT3 genes in 8,000 Finnish men to further explore the effects of SIRT3. They found a single nucleotide polymorphism of SIRT3 gene that was associated with reduced SIRT3 activity and an increased risk for developing metabolic syndrome. The mutation was found in 30% of their sample. The researchers noted that their “findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.”

“Finding a SIRT3 gene mutation linked to metabolic syndrome is a big step towards developing treatments for this increasingly common collection of obesity-related illnesses,” Dr Eric Verdin, a co-author of the study and senior investigator at the Gladstone Institute of Virology and Immunology and professor of medicine at the University of California, San Francisco, said in a statement to the press. “In the future, we hope to examine whether increasing SIRT3 activity can help decrease the symptoms of metabolic syndrome. We are also working to identify new drugs that can enhance the SIRT3 enzyme. Such drugs could be used in the future to stem the tide of the metabolic syndrome and its many complications.”

Dr Warner Greene, director, senior investigator, and the Nick and Sue Hellmann Distinguished Professor of Translational Medicine at the Gladstone Institute as well as professor of medicine, microbiology and immunology at the University of California, San Francisco, added, “Estimates indicate that one-third of Americans have the metabolic syndrome, and more develop it each year.” Dr Greene discussed the clinical implications of the study, saying, “By showing how the absence of SIRT3 can exacerbate obesity, Dr. Verdin’s group offers important clues concerning new ways to alleviate the symptoms of this American epidemic.”

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References:

Hirschey MD, Shimazu T, Jing E, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell. 2011; Aug 17 [Epub].
Holden A. Gladstone scientist identifies gene that exacerbates risk factors for heart disease and diabetes. Gladstone News. August 18, 2011.