Major pathways in which ABCA1 plays an important role for cholesterol transport in brains: (A) Reverse cholesterol transport pathway, (B) LXR/RXR pathway, and (C) SREBP2 pathway

Major pathways in which ABCA1 plays an important role for cholesterol transport in brains: (A) Reverse cholesterol transport pathway, (B) LXR/RXR pathway, and (C) SREBP2 pathway. In the reverse cholesterol transport pathway, free cholesterol is transported out of the macrophage to ApoA-1. ApoA-1 then becomes pre-B-HDL or nascent HDL. Nascent HDL then becomes mature HDL which is mediated by LCAT. LCAT then mediates cholesterol esterification of HDL into cholesterol ester (CE). The cholesterol esters are then taken up by SCARB1 receptors and taken up into hepatocytes. Cholesterol esters are then hydrolyzed to generate free cholesterol (FCh) in hepatocytes. In the LXR/RXR pathway, ligand LDL binds to receptor CD36, which oxidizes LDL into cholesterol esters. The cholesterol esters are converted into cholesterol, which is then converted into oxysterols. The oxysterols activate LXR/RXR, which then promotes cholesterol efflux from the nucleus, which then activates ABCA1 to transfer cholesterol out of the macrophage to Apo acceptors. In the SREBP2 pathway, SCAP transports SREBP2 from the ER to the Golgi apparatus. SREBP2 is then translocated to the sterol regulatory element in the nucleus. Then miR-33a is co-transcribed with SREBP2, which inhibits ABCA1 activity. By inhibiting ABCA1, cholesterol efflux is hindered, therefore cholesterol accumulates. However, inhibiting miR-33a would activate ABCA1 and promote cholesterol efflux

Publication

Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer’s Disease (2023) Marina Passero, et al. Int J Environ Res Public Health. 2023 Jul;20(13). Figure: F6. Homo sapiens

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