Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Fenglin Road, Shanghai 200032, People's Republic of China.
Development. 2023 Oct 15;150(20). doi: 10.1242/dev.201135. Epub 2023 Apr 11.
Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we demonstrate that the methionine adenosyltransferase gene Mat2a is essential for intestinal development and that the metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cell (IEC)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IEC apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspases 3 and 8 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in intestinal development and homeostasis in mice.
蛋氨酸对各种生物体的肠道发育和稳态都很重要。然而，其潜在的机制尚不清楚。在这里，我们证明了蛋氨酸腺苷转移酶基因 Mat2a 对肠道发育是必不可少的，而代谢物 S-腺苷-L-蛋氨酸（SAM）在肠道稳态中发挥着重要作用。肠上皮细胞（IEC）特异性敲除 Mat2a 表现出肠道发育受损和新生仔鼠致死。成年肠道中 Mat2a 的缺失会减少细胞增殖并引发 IEC 细胞凋亡，导致严重的肠道上皮萎缩和肠道炎症。在机制上，我们揭示了 SAM 通过抑制半胱天冬酶 3 和 8 的表达及其激活来维持分化上皮的完整性并保护 IEC 免受细胞凋亡。SAM 补充可改善有缺陷的肠道上皮，并依次减少炎症浸润。总之，我们的研究表明，蛋氨酸代谢及其中间代谢物 SAM 在小鼠的肠道发育和稳态中起着至关重要的作用。
