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Disruption of Retinoblastoma Protein Expression In the Intestinal Epithelium Impairs Lipid Absorption

Saturday, October 20, 2012
Napoleon Ballroom (Hilton Riverside)
Pamela M. Choi, MD1, Jun Guo, PhD1, Christopher R. Erwin, PhD1, Sylvia Wandu1, Brian DeBosch, MD, PhD2, Yan Xie3, Nicholas O. Davidson, MD3 and Brad W. Warner, MD1, (1)Pediatric Surgery, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO, (2)Pediatric Gastroenterology, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO, (3)Gastroenterology, Washington University School of Medicine, St Louis, MO

Purpose: We have previously demonstrated morphologic changes that mirror resection-induced adaptation (increases in villus height and crypt depth) in a strain of mice in which Retinoblastoma protein (Rb) expression is disrupted in the intestinal epithelium (Rb-IKO). The functional consequences of this augmented mucosal phenotype are presently unknown. The purpose of the present study therefore, was to test the hypothesis that greater mucosal surface area in Rb-IKO mice would be associated with enhanced intestinal function.


Methods: Villin-Cre mice were bred with Rb(flox/flox) mice to generate offspring with disrupted Rb expression in the intestinal epithelium (Rb-IKO). Fecal fat was determined by chloroform:methanol extraction, and fat absorption recorded by the difference between fecal fat and known enteral fat intake. Indirect Calorimetry was employed in individual mice to record 24-hr energy expenditure (EE) and respiratory quotient (RQ). Carbohydrate absorption was determined using ex-vivo jejunal ring assays with 14C-Fructose and 3H-2Deoxy-Glucose.

Results: Despite greater mucosal surface area, the Rb-IKO mice had impaired intestinal fat absorption (Figure 1). To test the significance of this finding, Rb-IKO and wild-type (WT) controls were placed on an adipogenic Western diet and body weights recorded for 54 weeks. Despite impaired fat absorption, weight gain was indistinguishable between the two groups (Figure 2). Similar to the lack of differences in weight gain, EE and RQ were not different (data not shown). Although 14C-Fructose uptake was similar, we found significantly increased 3H-2Deoxy-Glucose uptake in the Rb-IKO group (13.10.83 vs 11.60.60 pmol/mg/2min, p = 0.046).


Conclusion: Despite an expanded mucosal surface area, intestinal fat absorption is impaired and glucose uptake is enhanced in Rb-IKO mice. These findings underscore the importance of delineating structural/functional relationships in the gut and suggest a previously unknown role for Rb in the regulation of intestinal lipid and/or carbohydrate absorption.













Figure 1: Rb-IKO have significant increase in % fecal fat and a corresponding decrease in % fat absorption (* p < 0.05).










Figure 2: Average weight gain of Rb-IKO and WT littermates while on High Fat Diet