With a pair of papers describing the role for SIRT3 in diabetes and the metabolic syndrome published in the last week, a summary of these follows. The metabolic syndrome refers to a collection of metabolic abnormalities, including obesity, diabetes, increased blood lipids, and high blood pressure. The number of people with the metabolic syndrome is rising in the developed world and will lead to future increases in diabetes and cardiovascular disease. Sedentary lifestyles and high-fat “Western” diets contribute to the metabolic syndrome, however the cause is not fully understood. Thus, understanding the molecular mechanisms that cause it is critical public health problem. A genetic component is likely, and several genes have been implicated.
Dr. Matthew Hirschey, in collaboration with the laboratory of Eric Verdin, has focused on a new family of enzymes called the sirtuins that regulate a number of important cellular processes, including energy production. The seven human sirtuins (SIRT 1–7) are deacetylases. They remove a small chemical group from other enzymes. Adding or removing small chemical groups called acetylation is a common way that enzymes are turned on or off. Acetylation is increasingly recognized as an important regulatory mechanism. For example, acetylation controls the enzymatic activity of several mitochondrial metabolic enzymes. In fact, mitochondrial protein acetylation is regulated by the nutrition and by diet.
Dr. Hirschey and the Verdin Lab team have studied a sirtuin in particular called SIRT3. It is found in the mitochondria, the energy-producing site in cells. To better understand the role of SIRT3, they fed normal mice and mice that lack SIRT3 a high-fat diet. In the normal mice, they found that the proteins in liver mitochondria were hyperacetylated (i.e., they had many more acetyl groups). In addition, these mice had less SIRT3, and some important metabolic reactions were reduced, such as fat burning. Mice lacking SIRT3 became obese more rapidly and had many of the other characteristics of the metabolic syndrome, including insulin resistance (a precursor to diabetes), increased levels of blood lipids, and fatty livers.
In humans, the team identified a small change in the genetic code for the SIRT3 gene called a single nucleotide polymorphism. The polymorphism encodes a mutation in the SIRT3 gene that makes the enzyme less efficient. Intriguingly, this particular SNP was found more often in patients with the metabolic syndrome.
[LINK TO PAPER]
Dr. Enxuan Jing and the Kahn lab at the Joslin Section on Integrative Physiology and Metabolism at Harvard Medical School found SIRT3 is decreased in the skeletal muscle of humans and animals with diabetes by at least half, compared to those without diabetes and that this may contribute to development of insulin resistance, one of the earliest manifestations of the disease. Many studies have shown that the mitochondria don't work well in those with diabetes, and loss of SIRT3 contributes to this. When Sirt3 levels are low, as they are in the case of diabetes, the mitochondria of the cells are not as efficient in energy metabolism as they should be and generate what are known as reactive oxygen species (ROS), chemically reactive molecules containing oxygen, which create insulin resistance in the muscles.
[LINK TO PAPER]
Together, these findings show that loss of SIRT3 and increased mitochondrial protein acetylation are detrimental and contribute to the development of diabetes, insulin resistance, and the metabolic syndrome. These exciting findings suggest a potential new pathway for treating these devestating metabolic diseases.