De novo phosphatidylcholine synthesis in the small intestinal epithelium is required for normal dietary lipid handling and maintenance of the mucosal barrier
2022
Carlin, Stephanie | Kennelly, John P. | Fedoruk, Hailey | Quiroga, Ariel | Leonard, Kelly-Ann | Nelson, Randal | Thiesen, Aducio | Buteau, Jean | Lehner, Richard | Jacobs, René
Cytidine triphosphate:phosphocholine cytidylyltransferase-α (CTα) is the rate limiting enzyme in the major pathway for de novo phosphatidylcholine (PC) synthesis. When CTα is deleted specifically in intestinal epithelial cells of adult mice (CTαᴵᴷᴼ mice) fed a high-fat diet they present with weight loss, lipid malabsorption, and high postprandial GLP-1 levels. The current study aimed to characterize the changes that occur in the small intestines of CTαᴵᴷᴼ mice using transcriptomics and to determine whether intestinal function could be rescued in CTαᴵᴷᴼ mice. We found that impaired de novo PC synthesis in the gut is linked to lower abundance of transcripts related to lipid metabolism and higher abundance of transcripts related to ER stress and cell death, together with loss of goblet cells from the small intestinal epithelium. Furthermore, impaired movement of fatty acids from the intestinal lumen into enterocytes was observed in isolated intestinal sacs derived from CTαᴵᴷᴼ mice, a model that excludes factors such as bile, gastric emptying, the nervous system, and circulating hormones. Antibiotic treatment prevented acute weight loss and normalized jejunum TG concentrations after refeeding but did not prevent ER stress or loss of goblet cells in CTαᴵᴷᴼ mice. Dietary PC supplementation partially prevented loss of goblet cells but was unable to normalize jejunal TG concentrations after refeeding in CTαᴵᴷᴼ mice. High postprandial plasma GLP-1 levels were present in CTαᴵᴷᴼ mice regardless of antibiotic treatment, dietary PC content, or dietary fat content. Together, these data show that there is a specific requirement from de novo PC synthesis in maintaining small intestinal homeostasis, including dietary lipid uptake, normal hormone secretion, and barrier function.
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