The efforts of our last year focus on the phosphorylation regulation of SIRT1 and the role of SIRT1 in inflammatory diseases. As the leading member of the high-profile sirtuin family of proteins, the list of SIRT1 substrates is growing. However, how SIRT1 activity is regulated remains unclear. In one of our recent studies, we demonstrate that two anti-cell death protein kinases, DYRK1A and DYRK3, directly activate SIRT1 through phosphorylation modification. We discover that both DYRK1A and DYRK3 phosphorylate SIRT1 at a conserved amino acid residue. This modification increases SIRT1s activity, resulting in inhibition of cell death in response to environmental stress. This study adds a new layer in the regulatory network that regulates SIRT1 activity and has important implications in understanding the molecular mechanism of tumorigenesis and aging. A paper describing this study was published in Journal of Biological Chemistry, in April of 2010. Chronic inflammation is increasingly recognized as a causal factor leading to the development of obesity, insulin resistance, and type 2 diabetes. This low-grade inflammatory state is in part mediated by macrophages, phagocytc cells that engulf cellular debris and pathogens as part of the innate immune response. Utilizing a mouse model that specifically deleted SIRT1 gene in macrophages, we demonstrate that SIRT1 plays an important role in suppression of inflammation. Mice lacking SIRT1 in the macrophages display elevated local and systemic inflammation when challenged with bacterial endotoxin or a high-fat high-cholesterol diet. The elevated chronic inflammation in turn leads to the development of insulin resistance under obesity conditions. Our findings suggest that new therapeutic strategies designed to modulate SIRT1 activity may be beneficial for the treatment of age-associated metabolic diseases. A paper describing this project has been accepted for publication in Molecular and Cellular Biology, in July of 2010. In addition to our own research, we have collaborated with Dr. Anders Naar's group at Harvard University/MGH to study the role of SIRT1-ortholog in the regulation of lipid/cholesterol synthesis. This study demonstrated that SIRT1-like proteins play a critical and conserved role in the inhibition of fat synthesis in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders. A paper for this study has been published in Genes and Development, 2010.
Showing the most recent 10 out of 27 publications
