Details

Autor(en) / Beteiligte

• Li, Ying
• Chaurasia, Bhagirath
• Rahman, M. Mahidur
• Kaddai, Vincent
• Maschek, J. Alan
• Berg, Jordan A.
• Wilkerson, Joseph L.
• Mahmassani, Ziad S.
• Cox, James
• Wei, Peng
• Meikle, Peter J.
• Atkinson, Donald
• Wang, Liping
• Poss, Annelise M.
• Playdon, Mary C.
• Tippetts, Trevor S.
• Mousa, Esraa M.
• Nittayaboon, Kesara
• Anandh Babu, Pon Velayutham
• Drummond, Micah J.
• Clevers, Hans
• Shayman, James A.
• Hirabayashi, Yoshio
• Holland, William L.
• Rutter, Jared
• Edgar, Bruce A.
• Summers, Scott A.

Titel

Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2023-11, Vol.165 (5), p.1136-1150

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Cancers of the alimentary tract, including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one’s risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signal of nutritional excess, alter stem cell behaviors to influence cancer risk. We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism. SPT, which diverts dietary fatty acids and amino acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are up-regulated in human intestinal adenomas. They produce ceramides, which serve as prostemness signals that stimulate peroxisome-proliferator activated receptor-α and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors. Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk. These studies demonstrate that ceramides, which are products of fat and protein metabolism, may link unhealthy diets to the formation of intestinal polyps that seed cancer.