Mechanisms of hepatic chylomicron remnant clearance

Experimental evidence suggests that chylomicron remnants, the carriers of dietary lipids, are highly atherogenic and that their postprandial plasma concentration is directly correlated with the progression of coronary artery disease. Much interest has therefore focused on elucidation of the various steps involved in uptake of these lipoprotein particles from the circulation. Recently, gene targeting has been applied to generate mouse models with deficiencies in lipoprotein metabolism and to dissect the chylomicron remnant clearance pathway in vivo. These experiments, together with studies performed in cultured cells, have demonstrated that plasma clearance of chylomicron remnants is a two-step process. The lipoprotein particles are rapidly sequestered in the liver by binding to the heparan sulphate proteoglycan surface (HSPG) of hepatocytes. This constitutes a high-capacity reservoir for adsorbing large amounts of lipoproteins in the postprandial state. Binding to HSPG is facilitated by apolipoprotein E (apo E) molecules present on the surface of the remnant particles. Once bound to the hepatocellular surface, the remnants are further enriched with apo E secreted by the hepatocytes. They are then internalized by two lipoprotein receptors: the low-density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP). Characterization of this distinct clearance pathway for chylomicron remnants helps to direct further research towards developing an understanding of pathological abnormalities in postprandial lipoprotein metabolism.