The Fatty Acid Beta-Oxidation Pathway Is Important for Decidualization of Endometrial Stromal Cells in Both Humans and Mice1

Abstract

Embryo implantation and development requires the endometrial stromal cells (ESCs) to undergo decidualization. This differentiation process requires glucose utilization, and blockade of the pentose phosphate pathway inhibits decidualization of ESCs both in vitro and in vivo. Glucose and fatty acids are energy substrates for many cell types, and fatty acid beta-oxidation is critical for embryo implantation. Here, we investigated whether beta-oxidation is required for decidualization of ESCs. As assessed by marker gene expression, decidualization of human primary ESCs was blocked by reducing activity of carnitine calmitoyltransferase I, the rate-limiting enzyme in beta-oxidation, either by short hairpin RNA-mediated silencing or by treatment with the inhibitor etomoxir. Ranolazine (RAN), a partial beta-oxidation inhibitor, blocked early decidualization of a human ESC line. However, decidualization resumed after several days, most likely due to a compensatory up-regulation of GLUT1 expression and an increase in glucose metabolism. Simultaneous inhibition of the beta-oxidation pathway with RAN and the pentose phosphate pathway with glucosamine (GlcN) impaired in vitro decidualization of human ESCs more strongly than inhibition of either pathway alone. These findings were confirmed in murine ESCs in vitro, and exposure to RAN plus GlcN inhibited decidualization in vivo in a deciduoma model. Finally, intrauterine implantation of time-release RAN and GlcN pellets reduced pup number. Importantly, pup number returned to normal after the end of the pellet-active period. This work indicates that both fatty acids and glucose metabolism pathways are important for ESC decidualization, and suggests novel pathways to target for the design of future nonhormonal contraceptives.

Carnitine Traffic in Cells. Link With Cancer

“…In good agreement with this role, carnitine supply to patients with asthenozoospermia results in an increase of sperm motility. Concerning the regulation, CT2 seems to respond to progesterone stimuli (Sato et al, 2007); in line with this, CT2 is expressed at a higher level during the decidualization of the endometrium that is characterized by high progesterone levels (Sato et al, 2007;Tsai et al, 2014;Liang et al, 2018).…”

Trp53 deficient mice predisposed to preterm birth display region-specific lipid alterations at the embryo implantation site

“…Previously, we reported the down-regulation of several antioxidant enzymes and proteins involved in mitochondrial ATP production in the p53 d/d uterine tissue and suggested that Trp53 deficiency lead to mitochondrial dysfunction 7 . Specifically, the mitochondrial β-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice 28 . The β-oxidation pathway metabolizes FA to generate energy in the form of FADH2, NADH and acetyl CoA which are important coenzymes in ATP production.…”

A Crude Awakening: Effects of Crude Oil on Lipid Metabolism in Calanoid Copepods Terminating Diapause

“…Whether the presence of C. glacialis, along with Calanus finmarchicus, in some RNA-Seq samples influenced the gene expression patterns is difficult to discern with certainty. However, we may assume that the heterogeneity of the samples is somewhat balanced by the similarity in diapause behavior between the two species (reviewed by Baumgartner and Tarrant, 2017) and by the high conservation of the investigated lipid metabolic genes (e.g., Tsai et al, 2014). Indeed, the b-oxidation pathway is considered to be an evolutionarily well-conserved metabolic process (Schulz, 1991).…”