Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Metabolism of Carbohydrates and Lipids
Transport and Storage of Lipids
Metabolism of Plasma Lipoproteins — Catabolism of Chylomicrons and Very Low-Density Lipoproteins

Labeled chylomicrons are rapidly cleared from the bloodstream. In small animals (such as rats), the half-life of chylomicrons is only a few minutes; in larger animals and humans, it is longer but does not exceed 1 hour. Larger particles undergo Catabolism faster than smaller ones. Following intravenous administration of chylomicrons containing fatty acid-labeled triacylglycerols, about 80% of the label is recovered in adipose tissue, Heart, and Skeletal Muscle, and approximately 20% in the Liver. Since perfusion studies have demonstrated that only negligible amounts of native chylomicrons and VLDLs undergo catabolic conversion in the liver, the label detected therein must be of secondary origin, i.e., resulting from the metabolic transformation of chylomicrons in extrahepatic Tissues.

The Role of Lipoprotein Lipase

There is a strong correlation between the capacity of a tissue to incorporate Fatty acids from lipoprotein-associated triacylglycerols and The activity of the enzyme lipoprotein lipase. This enzyme is localized on the capillary walls, to which it is "anchored" by heparan sulfate proteoglycan chains. Lipoprotein lipase has been detected in extracts from The Heart, adipose tissue, Spleen, Lungs, renal medulla, aorta, Diaphragm, and Cytology/practical/135.html">Lactating mammary gland. It is virtually absent from circulating Blood; however, following heparin injection, the heparan sulfate linkage is disrupted, releasing lipoprotein lipase into the bloodstream, where it catalyzes the Hydrolysis of circulating triacylglycerols. Administration of large doses of heparin releases another lipase from the liver (heparin-releasing hepatic lipase). This enzyme differs in its properties from lipoprotein lipase and attacks chylomicrons less efficiently. The Physiological Role of hepatic lipase is not yet fully understood, but it has been shown to participate in the hepatic METABOLISM of HDL₂ (Fig. 26.6) and in The conversion of chylomicron remnants and VLDL remnants (see below).

Both Phospholipids and apolipoprotein C-II serve as Cofactors for lipoprotein lipase. Apo-C-II possesses a specific phospholipid-binding domain through which it attaches to the lipoprotein. Thus, chylomicrons and VLDLs supply both the substrate and the cofactors required for the enzyme that catalyzes their metabolism. Triacylglycerol hydrolysis occurs upon contact of the Lipoproteins with the endothelium-bound enzyme. During this process, triacylglycerol is sequentially converted into diacylglycerol and then into monoacylglycerol, which is further cleaved into free Fatty acid and glycerol. A fraction of the released fatty acids enters the bloodstream, where they bind to serum albumin, while the bulk of the free fatty acids is transported directly into tissues (Figs. 24.6 and 24.5). Cardiac lipoprotein lipase is characterized by a low K_m value for triacylglycerol, whereas the K_m of adipose tissue lipoprotein lipase is an order of magnitude higher. Upon transition from the fed to the fasted state, plasma triacylglycerol concentration decreases; under these conditions, cardiac lipoprotein lipase remains saturated with substrate, whereas the saturation of the adipose tissue enzyme declines. This results in a redistribution of substrate utilization in favor of the heart. A similar redistribution is observed during Lactation, when enzyme activity in adipose tissue decreases while mammary gland enzyme activity increases, thereby enhancing the uptake of lipoprotein-delivered long-chain fatty acids required for milk fat Biosynthesis.

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Fig. 26.6. High-density lipoprotein (HDL) metabolism. HRHL — heparin-releasing hepatic lipase; LCAT — lecithin-Cholesterol acyltransferase; LPL — lipoprotein lipase; C — cholesterol; CE — cholesteryl ester; PL — phospholipid; FFA — free fatty acids; A-I — apolipoprotein A-I. The figure illustrates the role of three Enzymes—HRHL, LCAT, and LPL—in the postulated HDL cycle, which mediates The transport of cholesterol from peripheral tissues to the liver. HDL₂ and HDL₃ — see Table 26.2. HRHL catalyzes the hydrolysis of phospholipids On the surface of HDL₂, releasing cholesterol that is subsequently taken up by the liver.

Formation of Lipoprotein Remnants

Under the action of lipoprotein lipase, chylomicrons lose about 90% of their triacylglycerols as well as apolipoprotein C, which is transferred back to HDLs, while apolipoprotein E is retained. The resulting chylomicron remnant has a diameter half that of the original chylomicron; its relative content of cholesterol and cholesteryl esters is correspondingly increased due to the depletion of triacylglycerols. VLDLs undergo a similar transformation, yielding VLDL remnants, which are also referred to as intermediate-density lipoproteins (IDLs).

The Role of the Liver

Chylomicron remnants are endocytosed by liver Cells, where cholesteryl esters and triacylglycerols undergo hydrolysis. This uptake is apparently mediated by specific apolipoprotein E receptors (Fig. 26.4). Approximately 50% of VLDL remnants enter the liver via this pathway, while the remaining 50% are converted into LDLs.

Experiments with apolipoprotein B-labeled VLDLs have demonstrated that VLDLs are precursors of IDLs, which in turn serve as precursors of LDLs. Calculations indicate that each of these lipoproteins contains one or two molecules of apolipoprotein B-100, which are conserved throughout these metabolic transformations. Each LDL particle is derived from a single VLDL particle (Fig. 26.5). The precise role of the liver in this process remains incompletely understood. In rats, the major portion of VLDL-derived apolipoprotein B is recovered in The Liver and only a minor fraction in LDLs. This is presumably because rat VLDLs contain apolipoprotein B-48 In addition to apolipoprotein B-100. If hepatic apolipoprotein E receptors have a higher affinity for apolipoprotein B-48 than for apolipoprotein B-100, this would explain why the majority of IDLs are taken up by the liver in rats, thereby restricting The formation of LDLs.