Protein phosphatase 4 promotes hepatic lipogenesis through dephosphorylating acetyl-CoA carboxylase 1 on serine 79
Protein phosphatase 4 promotes hepatic lipogenesis through dephosphorylating acetyl-CoA carboxylase 1 on serine 79
复制标题
蛋白磷酸酶 4 通过丝氨酸 79 上的乙酰辅酶 A 羧化酶 1 去磷酸化促进肝脂肪生成
DOI：
10.3892/mmr.2014.2397
复制
发表时间：
2014-10-01
影响因子：
3.4
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Meng, Xiangyu;Li, Meng;Li, Jian
可逆磷酸化在乙酰辅酶A羧化酶1（ACC 1）活性的调节中具有关键作用，ACC 1与从头脂肪生成相关。已经表明，AMP激活的蛋白激酶（AMPK）磷酸化ACC 1丝氨酸79和抑制其活性;然而，ACC 1去磷酸化的机制仍然难以捉摸。蛋白磷酸酶4（PP 4），一种普遍存在的丝氨酸/苏氨酸磷酸酶，调节多种细胞功能;然而，PP 4是否参与脂质代谢尚未阐明。在本研究中，PP 4被鉴定为ACC 1的新调节剂，ACC 1也参与肝脏脂肪生成。发现PP 4在db/db小鼠的肝脏中的表达显著增加。此外，在db/db小鼠的肝脏中观察到pACC 1-Ser 79/ACC 1水平降低并且发现高甘油三酯积累。此外，观察到PP 4过表达导致小鼠原代肝细胞中pACC 1-Ser 79/ACC 1比率降低，随后细胞内甘油三酯含量增加。PP 4在人HepG 2细胞中与pACC 1-Ser 79有直接相互作用。总之，本研究表明，PP 4可能是一种新的调节肝脏脂肪生成通过去磷酸化ACC 1丝氨酸79，这表明PP 4可能是一个有前途的治疗靶点在脂质代谢紊乱。
Reversible phosphorylation has a critical role in the regulation of the activity of acetyl-CoA carboxylase 1 (ACC1), which is associated with de novo lipogenesis. It has been shown that AMP-activated protein kinase (AMPK) phosphorylates ACC1 on serine 79 and inhibits its activity; however, the mechanism of ACC1 dephosphorylation remains elusive. Protein phosphatase 4 (PP4), a ubiquitous serine/threonine phosphatase, regulates a variety of cellular functions; however, whether PP4 is involved in lipid metabolism has yet to be elucidated. In the present study, PP4 was identified as a novel regulator of ACC1, which is also involved in hepatic lipogenesis. The expression of PP4 was found to be significantly increased in the livers of db/db mice. Furthermore, pACC1-Ser79/ACC1 levels were observed to be decreased and high triglyceride accumulation was found in the livers of db/db mice. Moreover, PP4 overexpression was observed to lead to a decreased pACC1-Ser79/ACC1 ratio and subsequently an increased intracellular triglyceride content in mouse primary hepatocytes. PP4 was also found to directly-interact with pACC1-Ser79 in human HepG2 cells. In conclusion, the present study showed that PP4 may be a novel regulator in hepatic lipogenesis through dephosphorylating ACC1 on serine 79, suggesting that PP4 may be a promising therapeutic target in lipid metabolism disorders.