The clearance of chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while ~20% goes to the liver. However, the liver does not metabolize native chylomicrons or VLDL significantly; thus, the fatty acids in the liver must be secondary to their metabolism in extrahepatic tissues.
Triacylglycerols of Chylomicrons & VLDL Are Hydrolyzed by Lipoprotein Lipase to Form Remnant Lipoproteins
Lipoprotein lipase is an enzyme located on the walls of blood capillaries, anchored to the endothelium by negatively charged proteoglycan chains of heparan sulfate. It has been found in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland, although it is not active in adult liver. It is not normally found in blood; however, following injection of heparin, lipoprotein lipase is released from its heparan sulfate–binding sites into the circulation. Hepatic lipase is bound to the sinusoidal surface of liver cells and is also released by heparin. This enzyme, however, does not react readily with chylomicrons or VLDL but is involved in chylomicron remnant and HDL metabolism.
Both phospholipids and apo C-IIare required as cofactors for lipoprotein lipase activity, while apo A-II and apo C-III act as inhibitors. Hydrolysis takes place while the lipoproteins are attached to the enzyme on the endothelium. Triacylglycerol is hydrolyzed progressively through a diacylglycerol to a monoacylglycerol and finally to FFA plus glycerol. Some of the released FFA return to the circulation, attached to albumin, but the bulk is transported into the tissue (see Figures 1 and 2). Heart lipoprotein lipase has a low Km for triacyl glycerol, about one-tenth of that for the enzyme in adipose tissue. This enables the delivery of fatty acids from triacylglycerol to be redirected from adipose tissue to the heart in the starved state when the plasma triacylglycerol decreases. A similar redirection to the mammary gland occurs during lactation, allowing uptake of lipoprotein triacylglycerol fatty acid for milk fat synthesis. The VLDL receptor plays an important part in the delivery of fatty acids from VLDL triacylglycerol to adipocytes by binding VLDL and bringing it into close contact with lipoprotein lipase. In adipose tissue, insulin enhances lipoprotein lipase synthesis in adipocytes and its translocation to the luminal surface of the capillary endothelium.
Fig1. Metabolic fate of chylomicrons. A, apolipoprotein A; B-48, apolipoprotein B-48; C, apolipoprotein C; C, cholesterol and cholesteryl ester; E, apolipoprotein E; HDL, high-density lipoprotein; HL, hepatic lipase; LRP, LDL-receptor–related protein; PL, phospholipid; TG, triacylglycerol. Only the predominant lipids are shown.
Fig2. Metabolic fate of very-low-density lipoproteins (VLDL) and production of low-density lipoproteins (LDL). A, apolipoprotein A; B-100, apolipoprotein B-100; C, apolipoprotein C; C, cholesterol and cholesteryl ester; E, apolipoprotein E; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; PL, phospholipid; TG, triacylglycerol. Only the predominant lipids are shown. It is possible that some IDL is also metabolized via the low-density lipoprotein receptor–related protein-1 (LRP-1.)
Reaction with lipoprotein lipase results in the loss of 70 to 90% of the triacylglycerol of chylomicrons and in the loss of apo C (which returns to HDL) but not apo E, which is retained. The resulting chylomicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol (see Figure 1). Similar changes occur to VLDL, with the formation of VLDL remnants (also called intermediate-density lipoprotein (IDL) (see Figure 2).
The Liver Is Responsible for the Uptake of Remnant Lipoproteins
Chylomicron remnants are taken up by the liver by receptor mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by apo E(see Figure 1), via two apo E-dependent receptors, the LDL (apo B-100, E) receptor and LDL receptor–related protein-1 (LRP-1). Hepatic lipase has a dual role: (1) it acts as a ligand to facilitate remnant uptake and (2) it hydrolyzes remnant triacylglycerol and phospholipid.
After VLDL has been converted to IDL, the remnant particles may be taken up by the liver directly via the LDL (apo B-100, E) receptor, or they may be further metabolized to LDL in the circulation. Only one molecule of apo B-100 is present in each of these lipoprotein particles, and this is conserved during the transformations. Thus, each LDL particle is derived from a single precursor VLDL particle (see Figure 2). In humans, a relatively large proportion of IDL forms LDL, accounting for the increased concentrations of LDL in humans compared with many other mammals.
