4.8 Article

Acetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function

Journal

NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-31725-2

Keywords

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Funding

  1. German Research Foundation [DFG LO1415/7-1]
  2. state of lower Saxony (R2N)
  3. Braukmann-Wittenberg-Herz-Stiftung
  4. Deutsche Forschungsgemeinschaft

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This study investigates the impact of de novo fatty acid synthesis on intestinal epithelial cells and reveals that inhibiting this process leads to the loss of crypt structures and a decline in intestinal epithelial stem cells. The findings highlight the importance of cellular lipogenesis in sustaining stem cell function and provide insights for colon cancer therapy.
Basic processes of the fatty acid metabolism have an important impact on the function of intestinal epithelial cells (IEC). However, while the role of cellular fatty acid oxidation is well appreciated, it is not clear how de novo fatty acid synthesis (FAS) influences the biology of IECs. We report here that interfering with de novo FAS by deletion of the enzyme Acetyl-CoA-Carboxylase (ACC)1 in IECs results in the loss of epithelial crypt structures and a specific decline in Lgr5(+) intestinal epithelial stem cells (ISC). Mechanistically, ACC1-mediated de novo FAS supports the formation of intestinal organoids and the differentiation of complex crypt structures by sustaining the nuclear accumulation of PPAR delta/beta-catenin in ISCs. The dependency of ISCs on cellular de novo FAS is tuned by the availability of environmental lipids, as an excess delivery of external fatty acids is sufficient to rescue the defect in crypt formation. Finally, inhibition of ACC1 reduces the formation of tumors in colitis-associated colon cancer, together highlighting the importance of cellular lipogenesis for sustaining ISC function and providing a potential perspective to colon cancer therapy. Here the authors report that inhibition of de novo fatty acid synthesis by deleting the enzyme Acetyl-CoA-Carboxylase 1 in the intestinal epithelium results in the loss of crypt structures and a specific decline in Lgr5+ intestinal epithelial stem cells.

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