Disruption of retinoblastoma protein expression in the intestinal epithelium impairs lipid absorption

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2014-05, Vol.306 (10), p.G909-G915
• Main Authors: Choi, Pamela M, Guo, Jun, Erwin, Christopher R, Wandu, Wambui S, Leinicke, Jennifer A, Xie, Yan, Davidson, Nicholas O, Warner, Brad W
• Format: Article
• Language: English
• Subjects: Animals; Diet; Diet, High-Fat; Genes; Homeostasis; Intestinal Absorption; Intestinal Mucosa - metabolism; Intestine, Small - surgery; Lipid Metabolism - genetics; Lipids; Mice; Mice, Knockout; Mucosal Biology; NMR; Nuclear magnetic resonance; Proteins; Retinoblastoma Protein - genetics; Triglycerides - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00067.2014

We previously demonstrated increased villus height following genetic deletion, or knockout, of retinoblastoma protein (Rb) in the intestinal epithelium (Rb-IKO). Here we determined the functional consequences of augmented mucosal growth on intestinal fat absorption and following a 50% small bowel resection (SBR). Mice with constitutively disrupted Rb expression in the intestinal epithelium (Rb-IKO) along with their floxed (wild-type, WT) littermates were placed on a high-fat diet (HFD, 42% kcal fat) for 54 wk. Mice were weighed weekly, and fat absorption, indirect calorimetry, and MRI body composition were measured. Rb-IKO mice were also subjected to a 50% SBR, followed by HFD feeding for 33 wk. In separate experiments, we examined intestinal fat absorption in mice with conditional (tamoxifen-inducible) intestinal Rb (inducible Rb-IKO) deletion. Microarray revealed that the transcriptional expression of lipid absorption/transport genes was significantly reduced in constitutive Rb-IKO mice. These mice demonstrated greater mucosal surface area yet manifested paradoxically impaired intestinal long-chain triglyceride absorption and decreased cholesterol absorption. Despite attenuated lipid absorption, there were no differences in metabolic rate, body composition, and weight gain in Rb-IKO and WT mice at baseline and following SBR. We also confirmed fat malabsorption in inducible Rb-IKO mice. We concluded that, despite an expanded mucosal surface area, Rb-IKO mice demonstrate impaired lipid absorption without compensatory alterations in energy homeostasis or body composition. 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 absorption.