In the past year, our efforts focus on the role of SIRT1 in intestinal tissue homeostasis, the function of SIRT1 phosphorylation in tissue-specific energy metabolism, as well as the role of SIRT1 in ES cell biology and animal development. As a highly conserved NAD+-dependent protein deacetylase, SIRT1 has been shown as a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although the functions of SIRT1 have been extensively studied in various metabolic tissues in recent years, the role of SIRT1 in nutrient absorption and sensing in small intestine, a key metabolic organ that provides the first interface between nutrients and animal metabolism, is still completely unknown. To elucidate the function of SIRT1 in intestinal metabolism, we recently generated a novel intestine-specific SIRT1 KO mouse model, SIRT1 IKO mice and showed that intestinal SIRT1 is an important regulator of ileal bile acid absorption that feedback modulates systemic bile acid homeostasis and cholesterol metabolism (Kazgan et al, Gastroenterology, 2014). In the past year, we further worked on the role of SIRT1 in intestinal tissue homeostasis. We discovered that deletion of SIRT1 specifically in intestinal epithelial cells stimulates cellular NF-kB signaling and Nrf2-mediated oxidative stress pathways, leading to hyperactivation of Paneth cells, enhanced intestinal inflammation, and altered gut microbiota. Under stress conditions induced by nutrients, chemicals, or aging, the extensive interaction between these three components increases the susceptibility to colitis. Importantly, we discovered that the mRNA levels of human SIRT1 were significantly decreased in human ulcerative colitis patients. Together with a recent report that a SIRT1 mutation that reduces its deacetylase activity is associated with colitis in humans, our findings support the hypothesis that SIRT1 is a key genetic factor that regulates the susceptibility to inflammatory bowel diseases (IBDs) in both humans and mice. This study uncovers a new role for SIRT1 in intestinal tissue homeostasis, and suggests that small molecules that activate SIRT1 maybe beneficial for treatment of human IBDs. A manuscript describing this exciting study is currently under review. In addition to colitis, we recently found that intestinal SIRT1 also plays an important role in the regulation of colon cancer. Intestinal SIRT1 deficiency leads to increased sensitivity to chemical-induced colon cancer formation, primarily through regulation of cancer cell metabolism and growth. In collaboration with researchers at UNC-Chapel Hill, we further discovered that increased expression of SIRT1 in colon cancer is associated with increased survival after surgery in human colon cancer patients. This study highlights the importance of SIRT1 in suppression of tumorigenesis. A manuscript describing this study is in preparation. SIRT1 is also a key regulator of animal development. However, despite the fact that the developmental defects of the first SIRT1 KO mouse model was reported more than 10 years ago, the molecular mechanisms underlying this important function of SIRT1 remain largely unclear. Using embryonic stem cells (ESCs) and mice as models, we recently discovered that SIRT1 contributes to the maintenance of homeostatic retinoic acid (RA) signaling and modulates mouse ESC differentiation. We further found that SIRT1 deficiency induced developmental defects is associated with elevated RA signaling in mice (Tang et al., Molecular Cell, 2014). In the past year, we continued our efforts in understanding the function of SIRT1 in stem cell biology and animal development, with focus on dissecting molecular mechanisms underlying SIRT1 deficiency induced developmental defects.

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9
Fiscal Year
2015
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Name
U.S. National Inst of Environ Hlth Scis
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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
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
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:
Tang, Shuang; Huang, Gang; Fan, Wei et al. (2014) SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation. Mol Cell 55:843-855
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

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