Research Article: Inhibition of Fatty Acid Synthase Reduces Blastocyst Hatching through Regulation of the AKT Pathway in Pigs

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Jing Guo, Nam-Hyung Kim, Xiang-Shun Cui, Qing-Yuan Sun.

http://doi.org/10.1371/journal.pone.0170624

Abstract

Fatty acid synthase (FASN) is an enzyme responsible for the de novo synthesis of long-chain fatty acids. During oncogenesis, FASN plays a role in growth and survival rather than acting within the energy storage pathways. Here, the function of FASN during early embryonic development was studied using its specific inhibitor, C75. We found that the presence of the inhibitor reduced blastocyst hatching. FASN inhibition decreased Cpt1 expression, leading to a reduction in mitochondria numbers and ATP content. This inhibition of FASN resulted in the down-regulation of the AKT pathway, thereby triggering apoptosis through the activation of the p53 pathway. Activation of the apoptotic pathway also leads to increased accumulation of reactive oxygen species and autophagy. In addition, the FASN inhibitor impaired cell proliferation, a parameter of blastocyst quality for outgrowth. The level of OCT4, an important factor in embryonic development, decreased after treatment with the FASN inhibitor. These results show that FASN exerts an effect on early embryonic development by regulating both fatty acid oxidation and the AKT pathway in pigs.

Partial Text

Fatty acid synthase (FASN) is a key enzyme catalyzing the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA. Fatty acids (FAs) are essential constituents of lipids involved in membrane biogenesis and are critical substrates in energy metabolism. There are two sources of FAs: exogenous FAs and endogenous FAs. The biosynthesis of endogenous FAs is catalyzed by FASN[1, 2]. The synthesis of FAs by FASN is initiated by the conversion of acetyl-CoA to malonyl-CoA. Malonyl-CoA is then used for FA synthesis and is involved in elongation[3]. FAs are important constituents of sphingolipids, ceramides, and glycolipids and are involved in many biological processes[4]. Under normal conditions, FASN-synthesized FAs are stored as triacylglycerols and are catabolized through FA oxidation (FAO) when necessary[5]. De novo FA synthesis is very active during embryogenesis and plays a critical role in embryonic development[6].

All chemicals used in this study were purchased from Sigma-Aldrich (St. Louis, MO, USA), unless otherwise indicated.

Our results showed that FASN inhibition blocks porcine embryonic development by causing a decrease in ATP content and inducing apoptosis. Therefore, we have shown that FASN acts as a critical regulator of blastocyst formation and hatching. We describe a molecular mechanism by which the FASN inhibitor induces the decrease in FA through the down-regulation of Cpt1. In addition, the regulation of apoptosis by FASN occurs via the AKT-p53 pathway.

 

Source:

http://doi.org/10.1371/journal.pone.0170624