title: Biliary Phospholipids Sustain Enterocyte Proliferation and Intestinal Tumor Progression via Nuclear Receptor Lrh1 in mice.
abstract: The proliferative-crypt compartment of the intestinal epithelium is enriched in phospholipids and accumulation of phospholipids has been described in colorectal tumors. Here we hypothesize that biliary phospholipid flow could directly contribute to the proliferative power of normal and dysplastic enterocytes. We used Abcb4-/-mice which lack biliary phospholipid secretion. We first show that Abcb4-/-mice are protected against intestinal tumorigenesis. At the molecular level, the transcriptional activity of the nuclear receptor Liver Receptor Homolog-1 (Lrh1) is reduced in Abcb4-/-mice and its re-activation re-establishes a tumor burden comparable to control mice. Feeding Abcb4-/-mice a diet supplemented with phospholipids completely overcomes the intestinal tumor protective phenotype, thus corroborating the hypothesis that the absence of biliary phospholipids and not lack of Abcb4 gene per se is responsible for the protection. In turn, phospholipids cannot re-establish intestinal tumorigenesis in Abcb4-/-mice crossed with mice with intestinal specific ablation of Lrh1, a nuclear hormone receptor that is activates by phospholipids. Our data identify the key role of biliary phospholipids in sustaining intestinal mucosa proliferation and tumor progression through the activation of nuclear receptor Lrh1.
authors.affiliation: Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy.|Fondazione Mario Negri Sud, Santa Maria Imbaro, 66030 Chieti, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Petruzzelli
authors.affiliation: Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy.|National Cancer Research Center, IRCCS Istituto Oncologico "Giovanni Paolo II", 70124 Bari, Italy.|INBB, National Institute for Biostuctures and Biosystems, 00136 Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piccinin
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro, 66030 Chieti, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy.|INBB, National Institute for Biostuctures and Biosystems, 00136 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Peres
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro, 66030 Chieti, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bellafante
authors.affiliation: Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy.|National Cancer Research Center, IRCCS Istituto Oncologico "Giovanni Paolo II", 70124 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D063646:Carcinogenesis / Q000473:pathology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D020895:Enterocytes / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D019938:Cyclin D1; D010743:Phospholipids; D018809:Proliferating Cell Nuclear Antigen; D018160:Receptors, Cytoplasmic and Nuclear; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C530105:Ccnd1 protein, mouse; C431936:Nr5a2 protein, mouse