29.4 Lipoproteins Transport Cholesterol and Triacylglycerols Throughout the Organism

Cholesterol and triacylglycerols are made primarily in the liver, but they are used by tissues throughout the body. How are these important but hydrophobic biochemicals shuttled through the bloodstream? Cholesterol and triacylglycerols are packaged into lipoprotein particles for transport through bodily fluids. Each particle consists of a core of hydrophobic lipids surrounded by a shell of more-polar lipids and proteins. The protein components (called apoproteins) have two roles: they solubilize hydrophobic lipids and contain cell-targeting signals. Some of the important lipoproteins and their properties are shown in Table 29.1.

Table 29.1 Properties of plasma lipoproteins
Abbreviations: TAG, triacylglycerol; CE, cholesterol ester; C, free cholesterol; PL, phospholipid; P, protein.

Lipoprotein particles are classified according to increasing density: chylomicrons, chylomicron remnants, very low density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). We considered chylomicrons, which transport dietary lipids, in the context of digestion.

Triacylglycerols and cholesterol in excess of the liver’s own needs are exported into the blood in the form of very low density lipoprotein. Triacylglycerols in VLDL are hydrolyzed by lipases on capillary surfaces, and the freed fatty acids are taken into the cells. The cholesterol-rich remnants, called intermediate-density lipoproteins, can be taken up by the liver for processing or converted into low-density lipoprotein by the removal of more triacylglycerols (Figure 29.13).

Figure 29.13: An overview of lipoprotein-particle metabolism. Fatty acids are abbreviated FFA.

Low-density lipoprotein is the major carrier of cholesterol in blood. This lipoprotein particle contains a core of cholesterol molecules linked by ester bonds to fatty acids. This core is surrounded by a shell of phospholipids and unesterified cholesterol. The shell also has a single copy of apoprotein B-100, which directs LDL to the proper cells (Figure 29.14). The role of LDL is to transport cholesterol to peripheral tissues and regulate de novo cholesterol synthesis at these sites, as described in the next section.

Figure 29.14: A schematic model of low-density lipoprotein. The LDL particle is approximately 22 nm (220 Å) in diameter.

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A different purpose is served by high-density lipoprotein, which picks up cholesterol released into the plasma from dying cells and from membranes undergoing turnover, a process termed reverse cholesterol transport. An acyltransferase in HDL esterifies these cholesterols, which are then returned by HDL to the liver.

Low-Density Lipoproteins Play a Central Role in Cholesterol Metabolism

Cholesterol metabolism must be precisely regulated to prevent atherosclerosis, the thickening of arterial walls with a subsequent loss of elasticity. The mode of control in the liver, the primary site of cholesterol synthesis, has already been discussed. The primary source of cholesterol for peripheral tissues is the low-density lipoprotein. As will be discussed in the Clinical Insight below, high concentrations of LDL in the blood play a role in setting the conditions for a heart attack. LDL is normally removed from the blood in a process called receptor-mediated endocytosis, which serves as a paradigm for the uptake of many molecules.

Receptor-mediated endocytosis of LDL is accomplished in three steps (Figure 29.15):

Figure 29.15: Receptor-mediated endocytosis. The process of receptor-mediated endocytosis is illustrated for low-density lipoprotein (LDL): (1) LDL binds to a specific receptor, the LDL receptor; (2) this complex invaginates to form an internal vesicle; (3) after separation from its receptor, the LDL-containing vesicle fuses with a lysosome, leading to the degradation of the LDL and the release of the cholesterol.

  1. Low-density lipoprotein binds to a receptor protein on the cell surface. Apoprotein B-100 on the surface of an LDL particle binds to a specific receptor protein on the plasma membrane of nonliver cells. The receptors for LDL are localized in specialized regions called coated pits, surrounded by a specialized protein called clathrin.

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  2. Figure 29.16: Endocytosis of low-density lipoprotein bound to its receptor. Micrographs of (A) LDL (conjugated to iron-laden ferritin for visualization, dark spots) bound to a coated-pit region on the surface of a cultured human fibroblast cell and (B) this region invaginating and fusing to form an endocytic vesicle.

    The cell internalizes the receptor–LDL complex. The plasma membrane in the vicinity of the complex folds in on itself (invaginates). The membrane then fuses to form an endocytic vesicle (called an endosome), enclosing the receptor–LDL complex (endocytosis) (Figure 29.16).

  3. Low-density lipoprotein is hydrolyzed in lysosomes. The vesicles containing LDL subsequently fuse with lysosomes, acidic vesicles that carry a wide array of degradative enzymes. The protein component of the LDL is hydrolyzed to free amino acids. The cholesteryl esters in the LDL are hydrolyzed by a lysosomal acid lipase. The LDL receptor itself usually returns unscathed to the plasma membrane. The round-trip time for a receptor is about 10 minutes; in its lifetime of about a day, it brings many LDL particles into the cell.

The released unesterified cholesterol can then be used for membrane biosynthesis or reesterified for storage inside the cell. The stored cholesterol must be reesterified because high concentrations of unesterified cholesterol disrupt the integrity of cell membranes.

The synthesis of the LDL receptor is itself subject to feedback regulation. Studies show that, when cholesterol is abundant inside the cell, new LDL receptors are not synthesized, blocking the uptake of additional cholesterol from plasma LDL.

!clinic! CLINICAL INSIGHT: The Absence of the LDL Receptor Leads to Familial Hypercholesterolemia and Atherosclerosis

High cholesterol levels promote atherosclerosis, which is the leading cause of death in industrialized societies. Cholesterol’s role in the development of atherosclerosis was elucidated by the study of familial hypercholesterolemia, a genetic disorder. Familial hypercholesterolemia is characterized by high concentrations of cholesterol and LDL in the plasma, about three to four times the desired amount. In familial hypercholesterolemia, cholesterol is deposited in various tissues because of the high concentration of LDL cholesterol in the plasma. Nodules of cholesterol called xanthomas are prominent in skin and tendons in those having high levels of LDL. LDL also accumulates under the endothelial cells lining the blood vessels. Of particular concern is the oxidation of the excess LDL to form oxidized LDL (oxLDL), which can instigate the inflammatory response by the immune system, a response that has been implicated in the development of cardiovascular disease. The oxLDL is taken up by immune-system cells called macrophages, which become engorged to form foam cells. These foam cells become trapped in the walls of the blood vessels and contribute to the formation of atherosclerotic plaques that cause arterial narrowing and lead to heart attacks (Figure 29.17).

Figure 29.17: The effects of excess cholesterol. Cross section of (A) a normal artery and (B) an artery blocked by a cholesterol-rich plaque.

The molecular defect in most cases of familial hypercholesterolemia is an absence or deficiency of functional receptors for LDL. Homozygotes have almost no functional receptors for LDL, whereas heterozygotes have about half the normal number. Consequently, the entry of LDL into liver and other cells is impaired, leading to an increased plasma level of LDL. Most homozygotes die of coronary artery disease in childhood. The disease in heterozygotes (1 in 500 people) has a milder and more variable clinical course.

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!clinic! CLINICAL INSIGHT: Cycling of the LDL Receptor Is Regulated

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protease, secreted by the liver, that plays a crucial role in the regulation of cycling of the LDL receptor. Despite the fact that PCSK9 is a protease, enzymatic activity of the protein is not required for cycling regulation. PCSK9 in the blood binds to a domain on the receptor that prevents the receptor from returning to the plasma membrane, and it is degraded in the lysosome along with its cargo.

Individuals having a mutation that reduces the amount of PCSK9 in the blood have greatly reduced levels of LDL in the blood and display an almost 90% reduction in the rate of cardiovascular disease. Presumably, reduced levels of PCSK9 allow more receptor cycling and more efficient removal of LDL from the blood. Much research is now being directed at inhibiting PCSK9 activity in individuals with high cholesterol levels.

!clinic! CLINICAL INSIGHT: HDL Seems to Protect Against Atherosclerosis

Although the events that result in atherosclerosis take place rapidly in patients with familial hypercholesterolemia, a similar sequence of events take place in people who develop atherosclerosis over decades. In particular, the formation of foam cells and plaques are especially hazardous occurrences. HDL and its role in returning cholesterol to the liver are important in mitigating these life-threatening circumstances.

HDL has a number of antiatherogenic properties, including the inhibition of LDL oxidation, but the best-characterized property is the removal of cholesterol from cells, especially macrophages. Earlier, we learned that HDL retrieves cholesterol from other tissues in the body to return the cholesterol to the liver for excretion as bile or in the feces. This transport, called reverse cholesterol transport, is especially important in regard to macrophages. Indeed, when the transport fails, macrophages become foam cells and facilitate the formation of plaques. Macrophages that collect cholesterol from LDL normally transport the cholesterol to HDL particles. The more HDL, the more readily this transport takes place and the less likely that the macrophages will develop into foam cells. Presumably, this robust reverse cholesterol transport accounts for the observation that higher HDL levels confer protection against arthrosclerosis.

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The importance of reverse cholesterol transport is illustrated by the occurrence of mutations that inactivate a cholesterol-transport proteins in endothelial cells and macrophages, ABCA1 (ATP-binding cassette transporter, subfamily A1) (Figure 12.17) Loss of activity of cholesterol-transport protein ABCA1 results in a very rare condition called Tangier disease, which is characterized by HDL deficiency, accumulation of cholesterol in macrophages, and premature atherosclerosis. Under normal conditions, the apoprotein component of HDL, apoA-I, binds to ABCA1 to facilitate LDL transport. Moreover, the interaction between apoA-I and ABCA1 initiates a signal transduction pathway in the endothelial cells that inhibits the inflammatory response. Another antiatherogenic property of HDL is due to the association of a serum esterase, paraoxanase, with HDL. Paraoxanase may destroy oxLDL, accounting for some of HDL’s ability to protect against coronary disease.

Until recently, high levels of HDL-bound cholesterol (“good cholesterol”) relative to LDL-bound cholesterol (“bad cholesterol”) were believed to protect against cardiovascular disease. This belief was based on epidemiological studies. However, a number of recent clinical trials revealed that increased levels of HDL-bound cholesterol had no protective effects at all. These studies do not discount the protective effects of HDL alone and illustrate the danger of equating free HDL and cholesterol-bound HDL.

!clinic! CLINICAL INSIGHT: The Clinical Management of Cholesterol Levels Can Be Understood at a Biochemical Level

Homozygous familial hypercholesterolemia can be treated only by a liver transplant. A more generally applicable therapy is available for heterozygotes and others with high levels of cholesterol. The goal is to reduce the amount of cholesterol in the blood by stimulating the single normal gene to produce more than the customary number of LDL receptors. We have already observed that the production of LDL receptors is controlled by the cell’s need for cholesterol. Therefore, the strategy is to deprive the cell of ready sources of cholesterol. When cholesterol is required, the amount of mRNA for the LDL receptor rises and more receptor is found on the cell surface. This state can be induced by a two-pronged approach. First, the reabsorption of bile salts from the intestine is inhibited. Bile salts are cholesterol derivatives that promote the absorption of dietary cholesterol and dietary fats. Second, de novo synthesis of cholesterol is blocked.

The reabsorption of bile is impeded by the oral administration of positively charged polymers, such as cholestyramine, that bind negatively charged bile salts and are not themselves absorbed. Cholesterol synthesis can be effectively blocked by a class of compounds called statins. A well-known example of such a compound is lovastatin, which is also called Mevacor (Figure 29.18). These compounds are potent competitive inhibitors of HMG-CoA reductase, the essential control point in the biosynthetic pathway. Plasma cholesterol levels decrease by 50% in many patients given both lovastatin and inhibitors of bile-salt reabsorption. Lovastatin and other inhibitors of HMG-CoA reductase are widely used to lower the plasma-cholesterol level in people who have atherosclerosis. Preliminary studies suggest that reducing levels of PCSK9 and HMG-CoA reductase activity may be an especially effective means of reducing cholesterol levels.

Figure 29.18: Lovastatin, a competitive inhibitor of HMG-CoA reductase. The part of the structure that resembles mevalonate is shown in red.

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