High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism.
High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism.
复制标题
高脂肪激活O-GlcNAc酰化并影响AMPK/ACC通路调节脂质代谢
作者：
Pang Y;Xu X;Xiang X;Li Y;Zhao Z;Li J;Gao S;Liu Q;Mai K;Ai Q
高脂肪饮食往往会导致脂肪过度沉积，对机体产生不利影响。然而，高脂肪引起肝脏脂肪沉积的机制尚不清楚。因此，本研究针对乙酰辅酶A羧化酶（ACC）来探讨高脂肪导致肝脏过度沉积的机制。在本研究中，克隆并表征了 ACC1 和 ACC2 的 ORF。同时，在高脂饮食（HFD）喂养的肝脏或用油酸（OA）孵育的肝细胞中，ACC1和ACC2的mRNA和蛋白质增加。与 OA 一起孵育的肝细胞中 ACC 的磷酸化也有所降低。此外，AICAR显着改善了ACC的磷酸化，而OA显着抑制了AMPK/ACC途径的磷酸化。进一步的实验表明，OA增加了整体O-GlcNAcylation，O-GlcNAcylation激动剂显着抑制AMPK和ACC的磷酸化。重要的是，由 HFD 或 OA 引起的脂质代谢紊乱可以通过治疗 ACC1 和 ACC2 双重抑制剂 CP-640186 来挽救。这些观察结果表明，高脂肪可能激活O-GlcNAcylation并影响AMPK/ACC途径来调节脂质合成，同时也强调了ACC在脂质稳态中作用的重要性。
A high-fat diet often leads to excessive fat deposition and adversely affects the organism. However, the mechanism of liver fat deposition induced by high fat is still unclear. Therefore, this study aimed at acetyl-CoA carboxylase (ACC) to explore the mechanism of excessive liver deposition induced by high fat. In the present study, the ORF of ACC1 and ACC2 were cloned and characterized. Meanwhile, the mRNA and protein of ACC1 and ACC2 were increased in liver fed with a high-fat diet (HFD) or in hepatocytes incubated with oleic acid (OA). The phosphorylation of ACC was also decreased in hepatocytes incubated with OA. Moreover, AICAR dramatically improved the phosphorylation of ACC, and OA significantly inhibited the phosphorylation of the AMPK/ACC pathway. Further experiments showed that OA increased global O-GlcNAcylation and agonist of O-GlcNAcylation significantly inhibited the phosphorylation of AMPK and ACC. Importantly, the disorder of lipid metabolism caused by HFD or OA could be rescued by treating CP-640186, the dual inhibitor of ACC1 and ACC2. These observations suggested that high fat may activate O-GlcNAcylation and affect the AMPK/ACC pathway to regulate lipid synthesis, and also emphasized the importance of the role of ACC in lipid homeostasis.