Abstract
The placenta participates in cholesterol biosynthesis and metabolism and regulates exchange between the maternal and fetal compartments. The fetus has high cholesterol requirements, and it is taken up and synthesized at elevated rates during pregnancy. In placental cells, the major source of cholesterol is the internalization of lipoprotein particles from maternal circulation by mechanisms that are not fully understood. As in hepatocytes, syncytiotrophoblast uptake of lipoprotein cholesterol involves lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI). Efflux outside the cells requires proteins such as the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. However, mechanisms associated with intracellular traffic of cholesterol in syncytiotrophoblasts are mostly unknown. In hepatocytes, uptaken cholesterol is transported to acidic late endosomes (LE) and lysosomes (LY). Proteins such as Niemann–Pick type C 1 (NPC1), NPC2, and StAR related lipid transfer domain containing 3 (STARD3) are required for cholesterol exit from the LE/LY. These proteins transfer cholesterol from the lumen of the LE/LY into the LE/LY-limiting membrane and then export it to the endoplasmic reticulum, mitochondria, or plasma membrane. Although the production, metabolism, and transport of cholesterol in placental cells are well explored, there is little information on the role of proteins related to intracellular cholesterol traffic in placental cells during physiological or pathological pregnancies. Such studies would be relevant for understanding fetal and placental cholesterol management. Oxidative stress, induced by generating excess reactive oxygen species (ROS), plays a critical role in regulating various cellular and biological functions and has emerged as a critical common mechanism after lysosomal and mitochondrial dysfunction. This review discusses the role of cholesterol, lysosomal and mitochondrial dysfunction, and ROS in the development and progression of hypercholesterolemic pregnancies.
Highlights
The placenta participates in cholesterol biosynthesis and metabolism and regulates exchange between the maternal and fetal compartments
If we focus on cholesterol trafficking disorders, a study by Vanier et al [40] first reported the potential role of pathological cholesterol transport on two lysosomal storage diseases (LSDs); Niemann–Pick type C 1 (NPC1), and Niemann–Pick type C 2 (NPC2)
maternal supraphysiological hypercholesterolemia (MSPH) placentas contain increased free cholesterol levels and reactive oxygen species (ROS); we propose that late endosomes (LE)/LY and mitochondrial function are compromised in MSPH placental cells
Summary
The placenta is a large organ that develops during pregnancy, enabling optimal fetal growth. It can adapt to diverse external factors both structurally and functionally. In adaptation problems during placenta development, fetal survival or fetal growth will be in danger, and diseases could develop [1]. Problems in the correct development of the placenta contribute to different diseases such as preeclampsia, which predispose the mother to lifelong diseases [2]. The different essential functions of the placenta include biosynthesis, metabolism, and transport of cholesterol, glucocorticoids, and sex hormones. This article compares the hepatic and placental cellular management of cholesterol under physiological conditions and provides an overview of the changes observed due to preeclampsia and maternal hypercholesterolemic pregnancies.
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