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 c oronary artery disease. Much interest has therefore focused on elucida tion of the various steps involved in uptake of these lipoprotein part icles from the circulation. Recently, gene targeting has been applied to generate mouse models with deficiencies in lipoprotein metabolism a nd 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-st ep process. The lipoprotein particles are rapidly sequestered in the l iver 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. finding to H SPG is facilitated by apolipoprotein E (apo E) molecules present on th e surface of the remnant particles. Once bound to the hepatocellular s urface, the remnants are further enriched with apo E secreted by the h epatocytes. They are then internalized by two lipoprotein receptors: t he low-density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP). Characterization of this distinct clearance pathway fo r chylomicron remnants helps to direct further research towards develo ping an understanding of pathological abnormalities in postprandial li poprotein metabolism. (C) 1997 by John Wiley & Sons, Ltd.