Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation
Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation
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DOI：
10.1016/j.devcel.2023.07.005
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发表时间：
2023-09-25
影响因子：
11.8
通讯作者：
Jiang，Wei
中科院分区：
文献类型：
--
作者：
Yi，Ying;Lan，Xianchun;Jiang，Wei
代谢重塑是细胞分化过程中最早发生的事件之一。在这里，我们将脂肪酸代谢定义为人类胚胎干细胞决定性内胚层分化的关键参与者。脂肪酸β-氧化增强，而脂肪生成减少，这是由于AMPK对脂肪生成酶乙酰辅酶A羧化酶的磷酸化。更重要的是，通过其抑制剂或AMPK激动剂抑制脂肪酸合成显著促进人内胚层分化，而阻断脂肪酸氧化损害分化。从机制上讲，减少的去新脂肪酸合成和增强的脂肪酸β-氧化都有助于细胞内乙酰辅酶A的积累，这保证了SMAD 3的乙酰化，并进一步引起核定位以促进内胚层分化。因此，我们目前的研究确定了早期分化过程中的脂肪酸合成/氧化转变，并提出了脂肪酸代谢在调节人内胚层分化中的指导作用。
Metabolic remodeling is one of the earliest events that occur during cell differentiation. Here, we define fatty acid metabolism as a key player in definitive endoderm differentiation from human embryonic stem cells. Fatty acid β-oxidation is enhanced while lipogenesis is decreased, and this is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase by AMPK. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist significantly promotes human endoderm differentiation, while blockade of fatty acid oxidation impairs differentiation. Mechanistically, reducedde novofatty acid synthesis and enhanced fatty acid β-oxidation both contribute to the accumulation of intracellular acetyl-CoA, which guarantees the acetylation of SMAD3 and further causes nuclear localization to promote endoderm differentiation. Thus, our current study identifies a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role for fatty acid metabolism in regulating human endoderm differentiation.