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

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

doi:10.1053/j.gastro.2023.07.017

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

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

13 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1136-1150
Number of pages	15
Journal	Gastroenterology
Volume	165
Issue number	5
DOIs	https://doi.org/10.1053/j.gastro.2023.07.017
Publication status	Published - Nov 2023

Keywords

Humans
Animals
Mice
Ceramides/metabolism
Fatty Acids
Sphingolipids/metabolism
Serine C-Palmitoyltransferase/metabolism
Adenoma

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10.1053/j.gastro.2023.07.017

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Li, Y., Chaurasia, B., Rahman, M. M., Kaddai, V., Maschek, J. A., Berg, J. A., Wilkerson, J. L., Mahmassani, Z. S., Cox, J., Wei, P., Meikle, P. J., Atkinson, D., Wang, L., Poss, A. M., Playdon, M. C., Tippetts, T. S., Mousa, E. M., Nittayaboon, K., Anandh Babu, P. V., ... Summers, S. A. (2023). Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk. Gastroenterology, 165(5), 1136-1150. https://doi.org/10.1053/j.gastro.2023.07.017

@article{b9bbc0f7b9c84fb08622be70497ea817,

title = "Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk",

abstract = "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.",

keywords = "Humans, Animals, Mice, Ceramides/metabolism, Fatty Acids, Sphingolipids/metabolism, Serine C-Palmitoyltransferase/metabolism, Adenoma",

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

year = "2023",

month = nov,

doi = "10.1053/j.gastro.2023.07.017",

language = "English",

volume = "165",

pages = "1136--1150",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "5",

}

Li, Y, Chaurasia, B, Rahman, MM, Kaddai, V, Maschek, JA, Berg, JA, Wilkerson, JL, Mahmassani, ZS, Cox, J, Wei, P, Meikle, PJ, Atkinson, D, Wang, L, Poss, AM, Playdon, MC, Tippetts, TS, Mousa, EM, Nittayaboon, K, Anandh Babu, PV, Drummond, MJ, Clevers, H, Shayman, JA, Hirabayashi, Y, Holland, WL, Rutter, J, Edgar, BA & Summers, SA 2023, 'Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk', Gastroenterology, vol. 165, no. 5, pp. 1136-1150. https://doi.org/10.1053/j.gastro.2023.07.017

TY - JOUR

T1 - Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk

AU - Li, Ying

AU - Chaurasia, Bhagirath

AU - Rahman, M Mahidur

AU - Kaddai, Vincent

AU - Maschek, J Alan

AU - Berg, Jordan A

AU - Wilkerson, Joseph L

AU - Mahmassani, Ziad S

AU - Cox, James

AU - Wei, Peng

AU - Meikle, Peter J

AU - Atkinson, Donald

AU - Wang, Liping

AU - Poss, Annelise M

AU - Playdon, Mary C

AU - Tippetts, Trevor S

AU - Mousa, Esraa M

AU - Nittayaboon, Kesara

AU - Anandh Babu, Pon Velayutham

AU - Drummond, Micah J

AU - Clevers, Hans

AU - Shayman, James A

AU - Hirabayashi, Yoshio

AU - Holland, William L

AU - Rutter, Jared

AU - Edgar, Bruce A

AU - Summers, Scott A

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

KW - Humans

KW - Animals

KW - Mice

KW - Ceramides/metabolism

KW - Fatty Acids

KW - Sphingolipids/metabolism

KW - Serine C-Palmitoyltransferase/metabolism

KW - Adenoma

U2 - 10.1053/j.gastro.2023.07.017

DO - 10.1053/j.gastro.2023.07.017

M3 - Article

C2 - 37541526

SN - 0016-5085

VL - 165

SP - 1136

EP - 1150

JO - Gastroenterology

JF - Gastroenterology

IS - 5

ER -

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

Abstract

Keywords

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