Human Placental Intracellular Cholesterol Transport: A Focus on Lysosomal and Mitochondrial Dysfunction and Oxidative Stress

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.

Keywords: cholesterol traffic; lysosome; mitochondria; oxidative stress; placenta.

Figure 1

Diagram of NPC1, NPC2, and STARD3 proteins in LDL-derived cholesterol transport. Cholesterol from the endocytic pathway is hydrolyzed in the lysosome by acid lipase to form free cholesterol, which binds to NPC2 and is delivered to NPC1. NPC1 takes the cholesterol out of the lysosome via glycocalyx molecules on the internal surface of the lysosomal membrane. Cholesterol then moves to the endoplasmic reticulum (ER) and is distributed to the rest of the cell. Alternatively, NPC2 can transfer cholesterol from LE/LY directly to STARD3, which mediates transport to mitochondria; however, the exact mechanism by which this occurs is unknown.

Figure 2

Diagram of endosomal cholesterol transport in the syncytiotrophoblast cells. In plasma, cholesterol is associated with different types of lipoprotein particles. LDL particles can interact with the plasma membrane of target cells via members of the LDLR family. The transfer of lipids between HDL and target cells is poorly understood. Several proteins and receptors bind HDL, such as SR-BI, which facilitates the uptake of cholesteryl esters. The receptor-ligand complexes dissociate after they enter acidic endosomal compartments. The receptors return to the plasma membrane, and lipoprotein particles enter the lysosomal pathway for degradation. Cholesterol incorporates into the endosomal/lysosomal membranes via NPC1 and NPC2. Cholesterol is transported to mitochondria for steroidogenesis via lipid transfer proteins such as STARD3. Cholesterol transport to other cellular targets, e.g., the plasma membrane, occurs via vesicular transport or cholesterol binding to various proteins. Alternatively, cholesterol can exit the STB via ABCA1 and ABCG1. ABCA1 stimulates cholesterol efflux to lipid-free apolipoproteins (predominantly ApoA-I, but also ApoE). Conversely, ABCG1 promotes the efflux of cholesterol and oxysterols to HDL. For detailed information, see text.