Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk.
Ceramides
Colorectal Cancer
Metabolism
Sphingolipids
Stem Cell
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
received:
13
09
2022
revised:
11
07
2023
accepted:
12
07
2023
pmc-release:
01
11
2024
medline:
26
10
2023
pubmed:
5
8
2023
entrez:
4
8
2023
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND & AIMS
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.
Identifiants
pubmed: 37541526
pii: S0016-5085(23)04837-0
doi: 10.1053/j.gastro.2023.07.017
pmc: PMC10592225
mid: NIHMS1922995
pii:
doi:
Substances chimiques
Ceramides
0
Fatty Acids
0
Sphingolipids
0
Serine C-Palmitoyltransferase
EC 2.3.1.50
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1136-1150Subventions
Organisme : NIH HHS
ID : S10 OD016232
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK108833
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115824
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL139451
Pays : United States
Organisme : NIDDK NIH HHS
ID : R44 DK116450
Pays : United States
Organisme : NIDDK NIH HHS
ID : R43 DK116450
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA272529
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK131609
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK130296
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112826
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA042014
Pays : United States
Organisme : NIH HHS
ID : S10 OD018210
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024761
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK122001
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK124326
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK091317
Pays : United States
Organisme : NIH HHS
ID : S10 OD021505
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA253744
Pays : United States
Informations de copyright
Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.
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