Fig. 1

Overview on the role of apolipoprotein E (APOE) in the three main pathways of plasma lipoprotein metabolism. In the exogenous pathway, chylomicrons (CM) are generated in the intestine from dietary fat and cholesterol and enter the systemic circulation, where they acquire APOE. CM are lipolyzed by lipoprotein lipase (LPL) and form CM remnants (CMR). Peripheral tissues, e.g., skeletal muscle and adipose tissue, take up released free fatty acids (FFA) and cholesterol. CMR undergo hepatic clearance after APOE-mediated binding to cell surface receptors, e.g., low density lipoprotein (LDL) receptor (LDLR) or LDLR-related protein (LRP) and heparan sulfate proteoglycan (HSPG) pathways. In the endogenous pathway, very low density lipoproteins (VLDL) are synthesized and secreted by the liver. LPL and hepatic lipase (HL) cause the release of FFA and the formation of VLDL remnants which can be cleared by the liver by APOE-mediated uptake (see above). Complete hydrolysis of VLDL results in the formation of LDL which lack APOE (LDL contain APOB-100 which mediates cellular uptake). The reverse cholesterol transport (RCT) enables excess cholesterol to be redirected from peripheral tissues to the liver via high density lipoproteins (HDL) that comprise APOE. APOE apolipoprotein E, CM chylomicron, CMR CM remnant, FFA free fatty acids, HDL high density lipoprotein, HL hepatic lipase, HSPG heparan sulfate proteoglycan, IDL intermediate density lipoprotein, LDL low density lipoprotein, LDLR LDL receptor, LPL lipoprotein lipase, LRP LDL receptor-related protein, RCT reverse cholesterol transport. Figure prepared according to [22, 23, 176]