Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China.
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
Drug Metab Dispos. 2019 Jun;47(6):582-591. doi: 10.1124/dmd.119.086439. Epub 2019 Mar 27.
l-Carnitine (l-Car) plays a crucial role in fatty acid -oxidation. However, the plasma l-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic -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 were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor (PPAR) 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 PPAR-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of l-Car and -hydroxybutyrate (an indicator of mitochondrial -oxidation), and mRNA levels of several enzymes involved in fatty acid -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 -oxidation decrease.
左旋肉碱（l-Car）在脂肪酸氧化中起着至关重要的作用。然而，女性在怀孕期间血液中的左旋肉碱浓度明显下降，但这种现象的潜在机制及其对母体肝脏氧化的影响尚未阐明。我们的结果表明，妊娠第 18 天（GD18）小鼠的血浆左旋肉碱水平明显低于非妊娠小鼠，GD18 小鼠的胎儿与母体血浆左旋肉碱比值平均为 3.0。肉碱/有机阳离子转运体 2（OCTN2）在小鼠和人胎盘组织中高表达，并随着妊娠的进展在人胎盘组织中上调，而肉碱转运体（CT）1、CT2 和氨基酸转运体 B 的表达水平极低。进一步的研究表明，肾脏过氧化物酶体增殖物激活受体（PPAR）和 OCTN2 的表达下调，肾脏左旋肉碱水平降低，而晚期妊娠小鼠的尿左旋肉碱排泄量低于非妊娠小鼠。同时，孕激素（与妊娠相关的激素）通过 PPAR 介导的途径下调肾脏 OCTN2 的表达，并抑制 OCTN2 的活性，但雌二醇、皮质酮和皮质醇则没有。出乎意料的是，GD18 小鼠的母体肝脏左旋肉碱和 -羟丁酸（线粒体氧化的指标）水平以及参与脂肪酸氧化的几种酶的 mRNA 水平均高于非妊娠小鼠。总之，OCTN2 介导的胎盘左旋肉碱转运在妊娠期间母体血浆左旋肉碱减少中起着主要作用，但随后并未导致母体肝脏脂肪酸氧化减少。
