title: Disruption of retinoblastoma protein expression in the intestinal epithelium impairs lipid absorption.
abstract: 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.
authors.affiliation: Division of Pediatric Surgery, St Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Choi
authors.affiliation: Division of Pediatric Surgery, St Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Division of Pediatric Surgery, St Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Erwin
authors.affiliation: Division of Pediatric Surgery, St Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Wambui S
authors.initials: WS
authors.lastname: Wandu
authors.affiliation: Division of Pediatric Surgery, St Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leinicke
authors.affiliation: Department of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
authors.affiliation: Division of Pediatric Surgery, St Louis Children's Hospital, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; brad.warner@wustl.edu.
authors.forename: Brad W
authors.initials: BW
authors.lastname: Warner
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000601:surgery; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016160:Retinoblastoma Protein / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; D014280:Triglycerides
keywords: CD36; fat metabolism; retinoblastoma protein
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