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 intestinal epithelial SIRT1 in mice age-dependently elicits NF-B signaling and other stress response pathways, and enhances spontaneous inflammation. Intestinal epithelial SIRT1 deficiency also alters the commensal gut microbial composition through altered bile acid metabolism and increases susceptibility to DSS-induced colitis. Consistently, the expression level of human SIRT1 is significantly reduced in human ulcerative colitis patients. However, remarkably, these SIRT1 deficiency-associated impairments are largely eliminated upon depletion of gut microbiota. Our findings define a crucial role of intestinal SIRT1 in mediating host-microbe interactions, and suggest that SIRT1-activating compounds may be therapeutically beneficial for the treatment of human IBD. A paper describing this study was just accepted for publication at Gastroenterology (Wellman, Metukuri et al., 2017, Gastroenterology) In addition to colitis, we recently found that intestinal SIRT1 also plays an important role in the regulation of colon cancer in a dose-dependent manner. Heterozygous deletion of SIRT1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance and cancer formation. In contrast, homozygous deletion of SIRT1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose-dependence in cells, intestine-specific SIRT1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific SIRT1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction but not deletion is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contributes to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1 small molecule activators/inhibitors based therapeutic strategies for cancers. A paper describing this study was published at early this year at Current Biology (Ren et al., 2017, Current Biology, 27:483-494) 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. Two manuscripts related to this direction are currently in revision. In addition to studies on SIRT1's role in the regulation of transcriptional networks in various critical metabolic processes in multiple tissues, we also elucidated the mechanisms by which SIRT1 is regulated. We have previously reported that SIRT1 can be phosphorylated at T522 by two anti-apoptotic members of the dual specificity tyrosine phosphorylation-regulated kinase (DYRK) in response to acute environmental stresses, and this modification activates its deacetylase activity independently of the cellular NAD+ level through preventing the formation of less-active SIRT1 oligomers/aggregates (Guo et al., 2010, JBC; Guo et al., 2012, Scientific Reports). To further investigate the role of this modification in vivo, we generated two transgenic mouse strains in which the wild type SIRT1 gene is replaced by a T522E (phosphorylation mimic) or a T522A (dephosphorylation mimic) mutation. Utilizing these two strains, we show that phosphorylation modification of T522 on SIRT1 is crucial for tissue-specific regulation of SIRT1 activity in mice. Dephosphorylation of T522 is critical for repression of its activity during adipogenesis. The phospho-T522 level is reduced during adipogenesis. Knocking-in a constitutive T522 phosphorylation mimic activates the -catenin/GATA3 pathway, repressing PPAR signaling, impairing differentiation of white adipocytes, and ameliorating high-fat diet induced dyslipidemia in mice. In contrast, phosphorylation of T522 is crucial for activation of hepatic SIRT1 in response to over-nutrition. Hepatic SIRT1 is hyperphosphorylated at T522 upon high-fat diet feeding. Knocking-in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis after high-fat diet feeding. In addition, the T522 dephosphorylation mimic impairs systemic energy metabolism. Our findings unveil an important link between environmental cues, SIRT1 phosphorylation, and energy homeostasis, and demonstrate that the phosphorylation of T522 is a critical element in tissue-specific regulation of SIRT1 activity in vivo. A paper describing this study was published this year at EMBO Reports (Lu et al., 2017, EMBO Reports).

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11
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2017
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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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