SIRT1 inhibits the mouse intestinal motility and epithelial proliferation.
Sirtuin 1 (SIRT1), a NAD(+)-dependent histone deacetylase, is involved in a wide array of cellular processes including glucose homeostasis, energy metabolism, proliferation and apoptosis, and immune response. However, it is unknown whether SIRT1 plays any physiological role in the regulation of intestinal homeostasis and motility. Thus the aim was to define SIRT1 expression and function in the gastrointestinal (GI) tract under physiological conditions. Forty 12-14-wk-old SIRT1 knockout (KO) and wild-type (WT) mice were fasted 21 h and/or refed 3 h. Fasted mice were injected intraperitoneally with bromodeoxyuridine (120 mg/kg body wt) 2 h before euthanasia. SIRT1 protein was localized to gastric and intestinal epithelial nuclei and was responsive to the nutritional status. SIRT1 was required for intestinal epithelial homeostasis. The SIRT1 KO mice showed enhanced crypt proliferation and suppressed villous apoptosis, resulting in increased intestinal villous height. In the SIRT1 KO intestine, the abundance of Forkhead box protein O1 and p53 protein decreased, whereas the subcellular localization of β-catenin protein accumulated mainly in the crypts. The SIRT1 KO mice showed accelerated gastric emptying rate with increased abundance of ghrelin mRNA and protein in the stomach. Moreover, the SIRT1 KO mouse intestine showed enhanced ex vivo spontaneous contraction. We concluded that, SIRT1 plays a critical role in the control of intestinal homeostasis (by promoting apoptosis and inhibiting proliferation) and gastrointestinal motility (by reducing gastric emptying and intestinal contractile activity), implicating a novel role for SIRT1.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston TX 77030, USA.
Yi
Y
Wang
Xuemei
X
Shi
Jian
J
Qi
Xiaojie
X
Li
Karen
K
Uray
Xinfu
X
Guan
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000378:metabolism*; D005746:Gastric Emptying / Q000235:genetics*; D005753:Gastric Mucosa / Q000378:metabolism*; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D054439:Ghrelin; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1