Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Department Isotope Biogeochemistry, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
Nat Commun. 2022 Jul 9;13(1):3998. doi: 10.1038/s41467-022-31725-2.
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 PPARδ/β-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.
脂肪酸代谢的基本过程对肠上皮细胞（IEC）的功能有重要影响。然而，虽然细胞脂肪酸氧化的作用已得到很好的认识，但尚不清楚从头合成脂肪酸（FAS）如何影响 IEC 的生物学特性。我们在这里报告，通过在 IEC 中缺失酶乙酰辅酶 A 羧化酶（ACC）1 来干扰从头 FAS，导致上皮隐窝结构的丧失和 Lgr5 肠上皮干细胞（ISC）的特异性下降。从机制上讲，ACC1 介导的从头 FAS 通过维持 ISC 中 PPARδ/β-catenin 的核积累，支持肠类器官的形成和复杂隐窝结构的分化。ISC 对细胞从头 FAS 的依赖性受到环境脂质可用性的调节，因为过量的外部脂肪酸供应足以挽救隐窝形成的缺陷。最后，ACC1 的抑制减少了结肠炎相关结肠癌中肿瘤的形成，这共同强调了细胞脂肪生成对于维持 ISC 功能的重要性，并为结肠癌治疗提供了一个潜在的视角。
