Maternal Plasma l-Carnitine Reduction During Pregnancy Is Mainly Attributed to OCTN2-Mediated Placental Uptake and Does Not Result in Maternal Hepatic Fatty Acid β-Oxidation Decline

Abstract

L-Carnitine (L-Car) plays a crucial role in fatty acid b-oxidation. However, the plasma L-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic b-oxidation have not yet been clarified. Our results showed that the plasma L-Car level in mice at gestation day (GD) 18 was significantly lower than that in nonpregnant 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 upregulated as gestation proceeds in human placenta, whereas expressions of carnitine transporter (CT) 1, CT2, and amino acid transporter B 0,+ were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor a (PPARa) and OCTN2 were downregulated and the renal L-Car level was reduced, whereas the urinary excretion of L-Car was lower in late pregnant mice than in nonpregnant mice. Meanwhile, progesterone (pregnancy-related hormone) downregulated the expression of renal OCTN2 via PPARa-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of L-Car and b-hydroxybutyrate (an indicator of mitochondrial b-oxidation), and mRNA levels of several enzymes involved in fatty acid b-oxidation in GD 18 mice were higher than that in nonpregnant mice. In conclusion, OCTN2 mediated L-Car transfer across the placenta played a major role in maternal plasma L-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid b-oxidation decrease.

Effects of single and repetitive valproic acid administration on the gene expression of placental transporters in pregnant rats: An analysis by gestational period

“…Human placental OCT3 (SLC22A3) expression during the first trimester was reported to be higher than that at term, whereas rat Oct3 (Slc22a3) increased with advancing gestation (Ahmadimoghaddam et al, 2013). Human placental OCTN2 (SLC22A5) expression during the first trimester was reported to be lower than that at term (Bai et al, 2019), whereas rat Octn2 (Slc22a5) was not changed with advancing gestation in the present study.…”

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine

“…OCTN1 and OCTN2 are expressed in the maternal-facing membranes of human syncytiotrophoblasts (9, 10), where OCTN2 mediates most maternal-fetal carnitine transport in humans (38,39). We used transporter-transfected cells to demonstrate that FTC is a substrate of OCTN1 but not OCTN2, and the OCTN1 inhibitor cimetidine markedly inhibited FTC accumulation in BeWo cells and PHTCs, which further confirmed that FTC was a substrate of OCTN1.…”

Plasma Free Amino Acid and Carnitine Levels in Pregnant Women with Hydatidiform Mole: A Case-Controlled Study

“…However, they have not simultanously measured the carnitine level changes in maternal plasma. Bai et al [19] have also investigated the reason of carnitine reduction and concluded that OCTN2 mediated L-Car transfer across placenta played a major role in maternal plasma L-Car reduction during pregnancy. We found higher carnitine levels in plasma of pregnant women with HM compared to the healthy pregnant women.…”