LIPOPROTEIN METABOLISM

Transport of Fat to Tissues: Lipoproteins

Chylomicrons constitute just one class oflipoproteins found in the bloodstream. These complexes play essential roles in the transport oflipids to tissues,either for energy storage or for oxidation.Free lipids are all but undetectable in blood. The polypeptide components oflipoproteins are called apoproteinsor apolipoproteins. These are synthesized mainly in the liver,though about 20% are produced in intestinal mucosal cells.

Classification and Functions of Lipoproteins

Distinct families of lipoproteins have been described,each of which plays defined roles in lipid transport. These families are classified in terms of their density, as determined by centrifugation (Table 17.1).

Lipoproteins in each class contain characteristic apoproteins and have distinctive lipid compositions. A total of 10 major apolipoproteins are found in human lipoproteins. Their properties are summarized in Table 17.2.

Each of these is encoded by a unique nuclear gene, with the interesting exception of apolipoproteins B-48 and B-100. Sequence analysis of these two proteins revealed that Apo B-48 (241,000 Da) is identical to the N-terminal portion of apo B-100.A single structural gene encodes both apo B-48 and apo B-100,which is transcribed into a 14,000-nucleotide mRNA (Figure 17.5).

FIGURE 17.5 RNA editing of the apolipoprotein B gene transcript. The APOB gene, composed of 29 exons, is transcribed to produce a ~14,000-nucleotide transcript. In liver, this mRNA is translated to give the 4536-amino acid apo B-100 product. In intestine, a cytidine deaminase converts the C residue in codon 2153 to U, changing the Gln codon to a stop codon. This edited mRNA is translated to give the 2152-amino acid apo B-48 product.

Reprinted from Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1494:1–13, A. Chester, J. Scott, S. Anant, N. Navaratnam, RNA editing: Cytidine to uridine conversion in apolipoprotein B mRNA. © 2000, with permission from Elsevier.

In liver, translation of the full-length open reading frame gives the 4536 amino acid apo B-100 (513,000 Da), which is secreted and assembled into low-density lipoprotein (LDL) particles. In intestine, where apo B-48 is expressed for chylomicron assembly, the apo B mRNA undergoes RNA editing: a cytidine deaminase found only in intestine specifically deaminates a single cytidine in them RNA, in codon 2153, converting it to uridine. This changes the codon from CAA (Gln) to UAA, a termination codon. Translation of this edited mRNA gives the shorter apo B-48.RNA editing is fairly widespread—its mechanism and control will be discussed in Chapter 29.

Because lipids are of much lower density than proteins, the lipid content of a lipoprotein class is inversely related to its density: The higher the lipid abundance, the lower the density. The standard lipoprotein classification includes, in increasing order of density: chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Some classification schemes recognize two classes of HDL, and in addition there is a quantitatively minor lipoprotein called very high-density lipoprotein (VHDL).

Despite their differences in lipid and protein composition, all lipoproteins share common structural features, notably a spherical shape that can be detected by electron microscopy. As shown in Figure 17.6, the hydrophobic parts, both lipid and apolar amino acid residues, form an inner core, and hydrophilic protein structures and polar head groups of phospholipids are on the outside.



FIGURE 17.6 Generalized structure of a plasma lipoprotein. The spherical particle, part of which is shown, contains neutral lipids in the interior and phospholipids, cholesterol, and protein at the surface.

Some apolipoproteins have specific biochemical activities other than their roles as passive carriers of lipid from one tissue to another. For instance, apo C-II is an activator of triacylglycerol hydrolysis by lipoprotein lipase, a cell surface glycoprotein that hydrolyzes triacylglycerols in lipoproteins. A human deficiency of apo C-II is associated with massive accumulation of chylomicrons and elevated triacylglycerol levels in blood. Other apoproteins target specific lipoproteins to specific cells by being recognized by receptors in the plasma membranes of these cells. Of great interest is an association of a variant form of apo E with increased risk for developing Alzheimer’s disease. The mechanism underlying this association is not yet understood, but there is a solid epidemiological link between high serum cholesterol at midlife and Alzheimer’s disease in later life, and apo E is the most abundant cholesterol transport protein in the central nervous system. There are three common allelic forms of apo E (E2,E3, and E4), and possessing at least one E4 allele is the major known genetic risk
factor for Alzheimer’s disease.

Following digestion and absorption of a meal, the lipoproteins help maintain in emulsified form some 500 mg of total lipid per 100 mL of human blood in the postabsorptive state. Of this 500 mg, typically about 120 mg is triacylglycerol,220 mg is cholesterol (two-thirds esterified with fatty acids, one-third free), and 160 mg is phospholipids, principally phosphatidylcholine and phosphatidylethanolamine. Indeed, following a high-fat meal, chylomicrons are so abundant in blood that they give the plasma a milky appearance.

Transport and Utilization of Lipoproteins

As noted previously, chylomicrons represent the form in which dietary fat is transported from the intestine to peripheral tissues, notably heart, muscle, and adipose tissue (see Figure 17.3). VLDL plays a comparable role for triacylglycerols synthesized in liver. The triacylglycerols in both of these lipoproteins are hydrolyzed to glycerol and fatty acids at the inner surfaces of capillaries in the peripheral tissues.This hydrolysis involves activation of the extracellular enzyme lipoprotein lipase by apoprotein C-II, a component of both chylomicron and VLDL (Figure 17.7). Lipoprotein lipase is a member of the serine esterase family, which includes pancreatic lipase and hormone sensitive lipase (HSL, an enzyme involved in the regulated mobilization of stored fat from adipose tissue—see page 721). This family is characterized by use of a catalytic triad of serine, histidine, and aspartate and an acyl-enzyme intermediate, similar to the serine proteases described in Chapter 11. Some of the released fatty acids are absorbed by nearby cells, while others, still rather insoluble, become complexed with serum albumin for transport to more distant cells. After absorption into the cell, the fatty acids derived from lipoprotein lipase action can be either catabolized to generate energy or, in adipose cells, used to resynthesize triacylglycerols. However, because adipocytes lack glycerol kinase, glycerol-3-phosphate for resynthesis of triacylglycerols must come from glycolysis. Glycerol is returned from adipocytes to the liver, for resynthesis of glucose by gluconeogenesis. Figure 17.8 summarizes overall aspects of lipoprotein metabolism and transport.

FIGURE 17.7 Binding of a chylomicron to lipoprotein lipase on the inner surface of a capillary. The chylomicron is anchored by lipoprotein lipase, which is linked by a polysaccharide chain to the lumenal surface of the endothelial cell. When activated by apoprotein C-II, the lipase hydrolyzes the triacylglycerols in the chylomicron, allowing uptake into the cell of the glycerol and the free fatty acids.

As a consequence of triacylglycerol hydrolysis in the capillaries, both chylomicrons and VLDL are degraded to protein-rich remnants. The IDL class of lipoprotein is derived from VLDL, and chylomicrons are degraded to what are simply called chylomicron remnants.Both classes of remnants are taken up by the liver through interaction with specific receptors and further degraded in liver lysosomes. Apoprotein B-100 is reused for synthesis of LDL (via IDL). As described in the next section, LDL is the principal form in which cholesterol is transported to tissues, and HDL plays the primary role in returning excess cholesterol from tissues to the liver for metabolism or excretion. The importance of lipoproteins as transport vehicles is evident from the fact that a major consequence of chronic liver cirrhosis is fatty liver degeneration, where the liver becomes engorged with fat. Because the liver is the major site of apolipoprotein synthesis, damage to this organ causes endogenously synthesized fat to accumulate there because it cannot be transported to peripheral tissues.

A major consequence of liver dysfunction is an inability to synthesize apolipoproteins and, hence, to transport fat out of the liver

FIGURE 17.8 Overview of lipoprotein transport pathways and fates.

Cholesterol Transport and Utilization in Animals

As you undoubtedly know, a primary risk factor predisposing to heart disease is an abnormally elevated level of cholesterol in the blood. Prolonged cholesterol accumulation contributes to the development of atherosclerotic plaques, fatty deposits that line the inner surfaces of coronary arteries. Recall from Table 17.1 that cholesterol in plasma lipoproteins exists both as the free sterol and as cholesterol esters. Esterification occurs at the cholesterol hydroxyl position with a long-chain fatty acid, usually unsaturated. Cholesterol esters are synthesized in plasma from cholesterol and an acyl chain on phosphatidylcholine (lecithin), through the action of lecithin:cholesterol acyltransferase (LCAT), an enzyme that is secreted from liver into the bloodstream, bound to HDL and LDL:

Cholesterol esters are considerably more hydrophobic than cholesterol itself.

Of the five lipoprotein classes, LDL is by far the richest in cholesterol. The amounts of cholesterol and cholesterol esters associated with LDL are typically about two-thirds of the total plasma cholesterol. In normal adults, total plasma cholesterol levels range from 3.5–6.7 mM (equivalent to of human plasma; total plasma cholesterol above 200 mg/100 mL is a major risk factor for heart disease). Approximately 40% of the weight of the LDL particle is cholesterol esters, and the total of esterified and free cholesterol approaches half the total weight. The LDL particle contains a single molecule of apoprotein B-100 as its primary protein component. Because cholesterol biosynthesis is confined primarily to the liver with some occurring also in intestine, LDL plays an important role in delivering cholesterol to other tissues.

CHAPTER 17 Lipid Metabolism I: Fatty Acids, Triacylglycerols, and Lipoproteins

Biochemistry - Mathews, Fourth Edition