Abstract
L-Carnitine (L-Car) plays a crucial role in fatty acid β-oxidation. However, the plasma L-Car concentration in women markedly declines during pregnancy, the underlying mechanism and the consequent on maternal hepatic β-oxidation has not been clarified yet. Our results showed that the plasma L-Car level in mice at gestation day (GD) 18 was significantly lower than that in non-pregnant mice, and the mean fetal-to-maternal plasma L-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and up-regulated as gestation proceeds in human placenta, while carnitine transporter (CT) 1, CT2 and amino acid transporter B0, + (ATB0, +) were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor α (PPARα) and OCTN2 were down-regulated, renal L-Car level was reduced while the urinary excretion of L-Car was lower in late pregnant mice than that in non-pregnant mice. Meanwhile, progesterone (pregnancy-related hormone) down-regulated the expression of renal OCTN2 via PPARα-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of L-Car, β-hydroxybutyrate (an indicator of mitochondrial β-oxidation) and mRNA level of several enzymes involved in fatty acid β-oxidation in GD 18 mice were higher than that in non-pregnant mice. In conclusion, OCTN2 mediated L-Car transfer across placenta played a major role in maternal plasma L-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid β-oxidation decrease.
- hormonal/endocrine regulation
- kidney/renal
- liver/hepatic
- peroxisome proliferator-activated receptors
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics