Er

membrane

CDP-choline CMP

GPAT LPAAT (acyl transferases)

CDP-choline CMP

GPAT LPAAT (acyl transferases)

Choline

made in the ER, beginning with the coupling of palmitoyl CoA and serine; the addition of a fatty acyl group to form N-acyl sphingosine (ceramide) also takes place in the ER. The subsequent addition of a polar head group to ceramide in the Golgi yields sphingomyelin, whose head group is phos-phorylcholine, and various glycosphingolipids, in which the head group may be a monosaccharide or a more complex oligosaccharide (see Figure 18-2). Some sphingolipid synthesis can also take place in mitochondria. In addition to serving as the backbone for sphingolipids, ceramide and its metabolic products are important signaling molecules that can influence cell growth, proliferation, endocytosis, resistance to stress, and apoptosis.

After their synthesis is completed in the Golgi, sphin-golipids are transported to other cellular compartments through vesicle-mediated mechanisms similar to those discussed in Chapter 17. In contrast, phospholipids, as well as cholesterol, can move between organelles by different mechanisms, described in Section 18.2.

Flippases Move Phospholipids from One Membrane Leaflet to the Opposite Leaflet

Even though phospholipids are initially incorporated into the cytosolic leaflet of the ER membrane, various phospholipids are asymmetrically distributed in the two leaflets of the ER membrane and of other cellular membranes (see Table 5-1). However, phospholipids spontaneously flip-flop from one leaflet to the other only very slowly, although they can rapidly diffuse laterally in the plane of the membrane. For the ER membrane to expand (growth of both leaflets) and have asymmetrically distributed phospholipids, its phospholipid components must be able to rapidly and selectively flip-flop from one membrane leaflet to the other.

The usual asymmetric distribution of phospholipids in membrane leaflets is broken down as cells (e.g., red blood cells) become senescent or undergo apoptosis. For instance, phosphatidylserine and phosphatidylethanolamine are preferentially located in the cytosolic leaflet of cellular membranes. Increased exposure of these anionic phospholipids on the exoplasmic face of the plasma membrane appears to serve as a signal for scavenger cells to remove and destroy old or dying cells. Annexin V, a protein that specifically binds to anionic phospholipids, can be fluorescently labeled and used to detect apoptotic cells in cultured cells and in tissues.

Although the mechanisms employed to generate and maintain membrane phospholipid asymmetry are not well understood, it is clear that flippases play a key role. These integral membrane proteins facilitate the movement of phos-pholipid molecules from one leaflet to the other (see Figure 18-4, step 4). One of the best-studied flippases is the mammalian ABCB4 protein, a member of the ABC superfamily of small-molecule pumps. As discussed in Section 18.3, ABCB4 is expressed in certain liver cells (hepatocytes) and moves phosphatidylcholine from the cytosolic to the exoplasmic leaflet of the plasma membrane for subsequent release into the bile in combination with cholesterol and bile acids. Several other ABC superfamily members participate in the cellular export of various lipids (Table 18-2).

ABCB4 was first suspected of having phospholipid flip-pase activity because mice with homozygous loss-of-function mutations in the ABCB4 gene exhibited defects in the secretion of phosphatidylcholine into bile. To determine directly if ABCB4 was in fact a flippase, researchers performed experiments on a homogeneous population of purified vesicles with ABCB4 in the membrane and with the cytosolic face directed outward. These vesicles were obtained by introducing cDNA encoding mammalian ABCB4 into a temperature-sensitive

TABLE 18-2 Selected Human ABC Proteins

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