▲ FIGURE 18-8 Proposed mechanisms of Golgi-independent transport of cholesterol and phospholipids between membranes. In mechanism (a), vesicles transfer lipids between membranes without passing through the Golgi apparatus. In mechanism (b), lipid transfer is a consequence of direct contact between membranes that is mediated by membrane-embedded proteins. In mechanism (c), transfer is mediated by small, soluble lipid-transfer proteins. Some evidence suggests that this mechanism does not account for a significant part of the Golgi-independent flow of phospholipids between membranes. [Adapted from F. R. Maxfield and D. Wustner, 2002, J. Clin. Invest. 110:891.]

an N-terminal targeting sequence that directs the protein to the mitochondrial outer membrane (Chapter 16) and a C-terminal START (StAR-related transfer) domain that has a cholesterol-binding hydrophobic pocket. Similar START domains are found in several proteins implicated in intracellular cholesterol transport, and these domains have been shown to promote cholesterol transfer in cultured cells. Mutations in the StAR gene can cause congenital adrenal hyperplasia, a lethal disease marked by a drastic reduction in the synthesis of steroid hormones. Some other proteins implicated in lipid transport, including the phosphatidylcholine-transfer protein already mentioned, also contain START domains.

A second well-established contributor to intracellular cholesterol movement is the Niemann-Pick C1 (NPC1) protein, an integral membrane protein located in the rapidly moving late endosomal/lysosomal compartment. Some of the multiple membrane-spanning segments of NPC1 form a sterol-sensing domain similar to that in HMG-CoA reductase. Mutations in NPC1 cause defects in intracellular cholesterol and glycosphingolipid transport and consequently in the regulation of cellular cholesterol metabolism. Cells without functional NPC1 or cells treated with a drug that mimics loss of NPC1 function accumulate excess cholesterol in the late endosomal/lysosomal compartment (Figure 18-9). Cholesterol transport in NPC1-deficient cells is restored by overexpression of Rab9, a small GTPase implicated in late endosomal vesicular transport (Chapter 17). This finding suggests that vesicular trafficking plays at least some role in NPC1-dependent cholesterol movement.

M EXPERIMENTAL FIGURE 18-9 Cells with nonfunctional Niemann-Pick C1 (NPC1) protein accumulate cholesterol in late endosomal/lysosomal vesicles. In three cells that express a transgene encoding a hybrid NPC1 protein linked to green fluorescent protein (GFP), the hybrid protein is revealed in the late endosomal/lysosomal compartment by its green fluorescence. Shown in this two-color fluorescence micrograph are cells that had been treated with a drug that inhibits NPC1 function. The cells were also stained with a blue-fluorescing cholesterol-binding drug called fillipin. Note the colocalization of cholesterol (blue) with the NPC1-GFP hybrid protein (green) on the surfaces of vesicles adjacent to the nucleus. Cells not expressing the hybrid NPC1 (blue only) are also seen. The accumulation of cholesterol in these vesicles in the absence of functional NPC1 suggests that late endosomal/lysosomal vesicles play a role in intracellular cholesterol trafficking. [From D. C. Ko et al., 2001, Mol. Biol. Cell 12:601; courtesy of D. Ko and M. Scott.]

In humans, defects in NPC1 function cause abnormal lipid storage in intracellular organelles, resulting in neurologic abnormalities, neurodegeneration, and premature death. Indeed, identification of the gene defective in such patients led to discovery of the NPC1 protein. I

The lipid compositions of different organelle membranes vary considerably (see Table 5-1). Some of these differences are due to different sites of synthesis. For example, a phospholipid called cardiolipin, which is localized to the mitochondrial membrane, is made only in mitochondria and little is transferred to other organelles. Differential transport of lipids also plays a role in determining the lipid compositions of different cellular membranes. For instance, even though cholesterol is made in the ER, the cholesterol concentration (cholesterol-to-phospholipid molar ratio) is ~1.5-13-fold higher in the plasma membrane than in other organelles (ER, Golgi, mitochondrion, lysosome). Although the mechanisms responsible for establishing and maintaining these differences are not well understood, the distinctive lipid composition of each membrane has a major influence on its physical properties (Chapter 5).

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