ABC Proteins Mediate Cellular Export of Phospholipids and Cholesterol

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The export of phospholipids and cholesterol can be simultaneous owing to the activity of various members of the ABC superfamily (see Table 18-2). The best-understood example of this phenomenon is in the formation of bile, an aqueous fluid containing phospholipids, cholesterol, and bile acids, which are derived from cholesterol. After export from liver cells, phospholipids, cholesterol, and bile acids form water-soluble micelles in the bile, which is delivered through ducts to the gallbladder, where it is stored and concentrated. In response to a fat-containing meal, bile is released into the small intestine to help emulsify dietary lipids and thus aid in their digestion and absorption into the body. As we shall see later, the alteration of biliary metabolism by drugs can be used to prevent heart attacks.

Figure 18-11 outlines the major transport proteins that mediate the secretion and movement of bile components. Three ABC proteins move phospholipids, cholesterol, and bile acids across the apical surface of liver cells into small ductules (step 1). One of these proteins, the ABCB4 flippase, flips phosphatidylcholine from the cytosolic leaflet to the

Human Bile Acids

▲ FIGURE 18-11 Major transport proteins in the liver and intestines taking part in the enterohepatic circulation of biliary lipids. The secretion of bile components and recycling of bile acids are mediated by a diverse array of transport proteins in liver cells (hepatocytes) and intestinal epithelial cells. Both of these polarized cell types import lipids across one surface and export them across the opposite surface. Step 1: Hepatocytes export lipids across their apical membranes into the bile by using three ATP-dependent ABC proteins: ABCB4 (phospholipids), ABCB11 (bile acids), and ABCG5/8 (sterols). Step 2: Intestinal epithelial cells import bile components and dietary lipids from the intestinal lumen by using the ileal bile acid transporter (IBAT), a Na+-linked symporter, and other less well defined transporters located in the apical membrane. Step 3: Imported bile acids are transported to the basolateral surface bound to intestinal bile acid-binding protein (I-BABP) and are exported into the blood with the aid of unknown transporters. Step 4: Bile acids returned to the liver in the blood are imported by NTCP another Na+-linked symporter. Step 5: Absorption of sterols by intestinal cells is reduced by ABCG5/8, which appears to pump plant sterols and cholesterol out of the cells and back into the lumen.

exoplasmic leaflet of the apical membrane in hepatocytes, as described earlier. The precise mechanism by which the excess phospholipid desorbs from the exoplasmic leaflet into the extracellular space is not understood. A related protein, ABCB11, transports bile acids, whereas the ABCG5 and ABCG8 "half" proteins combine into a single ABC protein (ABCG5/8) that exports sterols into the bile.

In the intestine the ileal bile acid transporter (IBAT) imports bile acids from the lumen into intestinal epithelial cells (step 2). IBAT is a Na+-linked symporter (see Figure 7-21) that uses the energy released by the movement of Na+ down its concentration gradient to power the uptake of about 95 percent of the bile acids. Those bile acids imported on the apical side of intestinal epithelial cells move intracellularly with the aid of intestinal bile acid-binding protein (I-BABP) to the basolateral side. There, they are exported into the blood by poorly characterized transport proteins (step 3) and eventually returned to liver cells by another Na+-linked symporter called NTCP (step 4). This cycling of bile acids from liver to intestine and back, referred to as the enterohepatic circulation, is tightly regulated and plays a major role in lipid homeostasis.

Because the amount of dietary cholesterol is normally low, a substantial fraction of the cholesterol in the intestinal lumen comes from the biliary cholesterol secreted by the liver. ABCG5/8 also is expressed in the apical membrane of intestinal epithelial cells, where it helps control the amounts of cholesterol and plant-derived sterols absorbed apparently by pumping excess or unwanted absorbed sterols out of the epithelial cells back into the lumen (see Figure 18-11, step 5 ). Partly as a result of this activity, only about 1 percent of dietary plant sterols, which are not metabolically useful to mammals, enter the bloodstream. Unabsorbed bile acids (normally <5 percent of the luminal bile acids) and unab-sorbed cholesterol and plant sterols are eventually excreted in the feces.

Inactivating mutations in the genes encoding ABCG5 or ABCG8 cause fi-sitosterolemia. Patients with this rare genetic disease absorb abnormally high amounts of both plant and animal sterols and their livers secrete abnormally low amounts into the bile. Indeed, findings from studies with ^-sitosterolemia patients first implicated these ABC proteins in cellular sterol export. I

Two other cell-surface transport proteins mediate the export of cellular cholesterol, phospholipid, or both: the ABC superfamily member ABCA1 and a homolog of the fatty acid transporter CD36 called SR-BI. These proteins will be described in detail shortly because of their important roles in lipoprotein metabolism.

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