Location: Children's Nutrition Research CenterTitle: SIRT1 inhibits the mouse intestinal motility and epithelial proliferation) Author
Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/24/2011
Publication Date: 1/1/2012
Citation: Wang, Y., Xuemei, S., Qi, J., Li, X., Uray, K., Guan, X. 2012. SIRT1 inhibits the mouse intestinal motility and epithelial proliferation. American Journal of Physiology - Gastrointestinal and Liver Physiology. 302:G207-G217. Interpretive Summary: The SIRT1 protein is involved in the regulation of diverse biological processes including cell proliferation, differentiation, and cell death, as well as glucose balance and energy metabolism, insulin secretion and sensitivity, and immune response. SIRT1's physiological relevance remains largely unknown in the gastrointestinal tract, which plays a key role in the control of energy balance. A major contributor of energy is glucose uptake by the gut, which is influenced by gastric emptying, which in turn is influenced by hormonal signals. Gastric emptying may serve as a key factor in the control of energy balance. We demonstrated that SIRT1 inhibits gastric emptying and intestinal contraction; SIRT1 suppresses cell proliferation and promotes cell apoptosis (death). This research suggests that SIRT1 activation is essential for the control of gastric emptying and intestinal contraction, which have nutritional consequences.
Technical Abstract: 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– to 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 Beta-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 conclude 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.