Biosynthesis of Cholesterol, Steroids, and Isoprenoids:- Cholesterol and Other Lipids Are Carried on Plasma Lipoproteins
Cholesterol and cholesteryl esters, like triacylglycerols and phospholipids, are essentially insoluble in water, yet must be moved from the tissue of origin to the tis sues in which they will be stored or consumed. They are carried in the blood plasma as plasma lipoproteins, macromolecular complexes of specific carrier proteins, apolipoproteins, with various combinations of phospholipids, cholesterol, cholesteryl esters, and triacyl glycerols.
Apolipoproteins (“apo” designates the protein in its lipid-free form) combine with lipids to form several classes of lipoprotein particles, spherical complexes with hydrophobic lipids in the core and hydrophilic amino acid side chains at the surface (Fig. 1a). Different combinations of lipids and proteins produce particles of different densities, ranging from chylomicrons to high-density lipoproteins. These particles can be separated by ultracentrifugation and visualized by electron microscopy (Fig. 1b).
FIGURE 1 Lipoproteins. (a) Structure of a low-density lipoprotein (LDL). Apolipoprotein B-100 (apoB-100) is one of the largest single polypeptide chains known, with 4,636 amino acid residues (Mr 513,000). (b) Four classes of lipoproteins, visualized in the electron microscope after negative staining. Clockwise from top left: chylomicrons, 50 to 200 nm in diameter; VLDL, 28 to 70 nm; HDL, 8 to 11 nm; and LDL, 20 to 25 nm. For properties of lipoproteins, see Table 21–2.
Each class of lipoprotein has a specific function, determined by its point of synthesis, lipid composition, and apolipoprotein content. At least nine different apolipoproteins are found in the lipoproteins of human plasma (Table 21–3), distinguishable by their size, their reactions with specific antibodies, and their characteristic distribution in the lipoprotein classes. These protein components act as signals, targeting lipoproteins to specific tissues or activating enzymes that act on the lipoproteins. Chylomicrons, discussed in Chapter 17 in connection with the movement of dietary triacylglycerols from the intestine to other tissues, are the largest of the lipoproteins and the least dense, containing a high proportion of triacylglycerols . Chylomicrons are synthesized in the ER of epithelial cells that line the small intestine, then move through the lymphatic system and enter the bloodstream via the left subclavian vein. The apolipoproteins of chylomicrons include apoB-48 (unique to this class of lipoproteins), apo E, and apoC-II (Table 21–3). ApoC-II activates lipoprotein lipase in the capillaries of adipose, heart, skeletal muscle, and lactating mammary tissues, allowing the release of free fatty acids to these tissues. Chylomicrons thus carry dietary fatty acids to tissues where they will be consumed or stored as fuel (Fig. 1). The remnants of chylomicrons (depleted of most of their triacylglycerols but still containing cholesterol, apoE, and apoB-48) move through the bloodstream to the liver. Receptors in the liver bind to the apoE in the chylomicron remnants and mediate their uptake by endocytosis. In the liver, the remnants release their cholesterol and are degraded in lysosomes.
FIGURE 21–40 Lipoproteins and lipid transport. (a) Lipids are transported in the bloodstream as lipoproteins, which exist as several variants that have different functions, different protein and lipid compositions (see Tables 21–2, 21–3), and thus different densities. Dietary lipids are packaged into chylomicrons; much of their triacylglycerol content is released by lipoprotein lipase to adipose and muscle tissues during transport through capillaries. Chylomicron remnants (containing largely protein and cholesterol) are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissue by VLDL. Extraction of lipid from VLDL (along with loss of some apolipoproteins) gradually con verts some of it to LDL, which delivers cholesterol to extrahepatic tissues or returns to the liver. The liver takes up LDL, VLDL remnants, and chylomicron remnants by receptor-mediated endocytosis. Excess cholesterol in extrahepatic tissues is transported back to the liver as HDL. In the liver, some cholesterol is converted to bile salts. (b) Blood plasma samples collected after a fast (left) and after a high-fat meal (right). Chylomicrons produced after a fatty meal give the plasma a milky appearance.
When the diet contains more fatty acids than are needed immediately as fuel, they are converted to triacylglycerols in the liver and packaged with specific apolipoproteins into very-low-density lipoprotein (VLDL). Excess carbohydrate in the diet can also be converted to triacylglycerols in the liver and exported as VLDLs (Fig. 21–40a). In addition to triacylglycerols, VLDLs contain some cholesterol and cholesteryl esters, as well as apoB-100, apoC-I, apoC-II, apoC-III, and apo E (Table 21–3). These lipoproteins are transported in the blood from the liver to muscle and adipose tissue, where activation of lipoprotein lipase by apoC-II causes the release of free fatty acids from the VLDL triacyl glycerols. Adipocytes take up these fatty acids, recon vert them to triacylglycerols, and store the products in intracellular lipid droplets; myocytes, in contrast, primarily oxidize the fatty acids to supply energy. Most VLDL remnants are removed from the circulation by hepatocytes. The uptake, like that for chylomicrons, is receptor-mediated and depends on the presence of apoE in the VLDL remnants (Box 21–3describes a link between apoE and Alzheimer’s disease). The loss of triacylglycerol converts some VLDL to VLDL remnants (also called intermediate density lipoprotein, IDL); further removal of triacylglycerol from VLDL produces low-density lipoprotein (LDL) (Table 21–2). Very rich in cholesterol and cholesteryl esters and containing apoB-100 as their major apolipoprotein, LDLs carry cholesterol to extrahepatic tis sues that have specific plasma membrane receptors that recognize apoB-100. These receptors mediate the uptake of cholesterol and cholesteryl esters in a process described below. The fourth major lipoprotein type, high-density lipoprotein (HDL), originates in the liver and small intestine as small, protein-rich particles that contain relatively little cholesterol and no cholesteryl esters (Fig. 1). HDLs contain apoA-I, apoC-I, apoC-II, and other apolipoproteins (Table 21–3), as well as the enzyme lecithin-cholesterol acyl transferase (LCAT), which catalyzes the formation of cholesteryl esters from lecithin (phosphatidylcholine) and cholesterol (Fig. 2). LCAT on the surface of nascent (newly forming) HDL particles converts the cholesterol and phos phatidylcholine of chylomicron and VLDL remnants to cholesteryl esters, which begin to form a core, trans forming the disk-shaped nascent HDL to a mature, spherical HDL particle. This cholesterol-rich lipoprotein then returns to the liver, where the cholesterol is un loaded; some of this cholesterol is converted to bile salts.
FIGURE 2 Reaction catalyzed by lecithin-cholesterol acyl trans ferase (LCAT). This enzyme is present on the surface of HDL and is stimulated by the HDL component apoA-I. Cholesteryl esters accumulate within nascent HDLs, converting them to mature HDLs.
HDL may be taken up in the liver by receptor mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective trans fer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21–40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL interacts with an active transporter, the ABC1 protein, in a cholesterol-rich cell. The apoA-I (and presumably the HDL) is taken up by endocytosis, then resecreted with a load of cholesterol, which it transports to the liver. The ABC1 protein is a member of a large family of multidrug transporters, sometimes called ABC trans porters because they all have ATP-binding cassettes; they also have two transmembrane domains with six transmembrane helices (Chapter 11). These proteins actively transport a variety of ions, amino acids, vita mins, steroid hormones, and bile salts across plasma membranes. The CFTR protein that is defective in cys tic fibrosis is another member of this ABC family of multidrug transporters.
