Protein phosphatase 4 promotes hepatic lipogenesis through dephosphorylating acetyl-CoA carboxylase 1 on serine 79

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.