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.

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Huang, He; Tang, Shuang; Ji, Ming et al. (2018) EP300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol Cell 70:663-678.e6
Wang, Yongbin; Gan, Guifang; Wang, Bocheng et al. (2017) Cancer-associated Fibroblasts Promote Irradiated Cancer Cell Recovery Through Autophagy. EBioMedicine 17:45-56
Tang, Shuang; Fang, Yi; Huang, Gang et al. (2017) Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J 36:3175-3193
Kwon, Sanghoon; Seok, Sunmi; Yau, Peter et al. (2017) Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3. J Biol Chem 292:17312-17323
Choi, Sung E; Kwon, Sanghoon; Seok, Sunmi et al. (2017) Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver. Mol Cell Biol 37:
Ren, Natalie S X; Ji, Ming; Tokar, Erik J et al. (2017) Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development. Curr Biol 27:483-494
Wellman, Alicia S; Metukuri, Mallikarjuna R; Kazgan, Nevzat et al. (2017) Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota. Gastroenterology 153:772-786
Lu, Jing; Xu, Qing; Ji, Ming et al. (2017) The phosphorylation status of T522 modulates tissue-specific functions of SIRT1 in energy metabolism in mice. EMBO Rep 18:841-857
Kazgan, Nevzat; Metukuri, Mallikarjuna R; Purushotham, Aparna et al. (2014) Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1?-FXR signaling and alters systemic bile acid homeostasis. Gastroenterology 146:1006-16
Yin, Huquan; Hu, Ming; Liang, Xiaomei et al. (2014) Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 146:801-11

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