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.
Highlights
The crypt compartment of the intestinal mucosa is enriched in total phospholipids, when compared to mid-villus and villus-tip regions[3], and isolated crypt cells display increased lipid synthesis compared to upper villus cells[4], suggesting a role for phospholipids in proliferating enterocytes
Liver Receptor Homolog 1 (LRH1) is a nuclear receptor highly expressed in the intestinal crypts[18], where it promotes mucosa regeneration and initiation of intestinal tumorigenesis[15,19]
In line with the recently reported activity of phospholipids as endogenous ligands for Lrh[120–22], absence of biliary phospholipids in Abcb4−/− mice resulted in nearly halved mRNA levels of Lrh[1], together with a severe relative fold reduction in expression levels of its target genes Small Heterodimer Partner (Shp) and Intestinal Bile Acid Binding Protein (Ibabp) (Fig. 1f)
Summary
The crypt compartment of the intestinal mucosa is enriched in total phospholipids, when compared to mid-villus and villus-tip regions[3], and isolated crypt cells display increased lipid synthesis compared to upper villus cells[4], suggesting a role for phospholipids in proliferating enterocytes. If previous study described Lrh[1] as constitutively active, recently the interaction between specific phospholipids and nuclear www.nature.com/scientificreports/. We used Abcb4−/− mice[17], which lack the hepatic transporter responsible for the flippase and active secretion of phospholipids across the hepatocyte canalicular membrane into bile. These mice have absence of biliary derived intestinal phospholipids with lower intraluminal phospholipid content. We observe that Lrh[1] activation due to the presence of phospholipids leads to a significant increase in tumor number and size in two distinct models of intestinal carcinogenesis. Intestinal phospholipid accumulation promotes enterocyte regeneration and tumor progression
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