Intracellular Cholesterol Transport and Compartmentation

Liscum, Laura; Underwood, Kathryn

doi:10.1074/jbc.270.26.15443

Cited by 252 publications

(216 citation statements)

References 60 publications

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“…Another class of functional role for the cholesterol-induced membrane domains comes from the kinetic evidence that the transport of cholesterol itself, both through and between membranes, may occur through specific domains (Liscum & Underwood, 1995). The regulation of the size and properties of these domains may control cholesterol transport and accumulation in cells (Schroeder et al, 1991;Bretscher & Munro, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Cholesterol is one of the membrane components that is found, more often than not, distributed nonrandomly in structural and kinetic domains or pools in both biological and model membranes (Yeagle, 1985;Gennis, 1989;Schroeder et al, 1991;Liscum & Underwood, 1995). The reason for this lies in the rather unusual chemical structure of cholesterol that can by no means be considered a representative component of the "bulk" membrane (see Figure 1).…”

mentioning

confidence: 99%

“…Although the basic tenets of this model have stood the test of time, one of its implicit assumptions, that the lipid molecules merely provide the milieu for the membrane proteins and that they are distributed uniformly throughout the bilayer, has been found to be not quite true. In fact, current evidence points out that both transverse and lateral regionalization, which can be described in terms of micro-and macrodomains, are common features of many biological membranes (Curtain et al, 1988;Edidin, 1992;Tocanne, 1992;Glaser, 1993;Jacobson et al, 1995).Cholesterol is one of the membrane components that is found, more often than not, distributed nonrandomly in structural and kinetic domains or pools in both biological and model membranes (Yeagle, 1985;Gennis, 1989;Schroeder et al, 1991;Liscum & Underwood, 1995). The reason for this lies in the rather unusual chemical structure of cholesterol that can by no means be considered a representative component of the "bulk" membrane (see Figure 1).…”

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confidence: 99%

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Membrane Organization at Low Cholesterol Concentrations: A Study Using 7-Nitrobenz-2-oxa-1,3-diazol-4-yl-Labeled Cholesterol

1996

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Cholesterol is most often found distributed nonrandomly in the plane of the bilayer, giving rise to cholesterol-rich and -poor domains. Many of these domains are thought to be crucial for the maintenance of membrane structure and function. However, such well-characterized domains generally occur in the membranes that contain relatively large amounts of cholesterol. Cholesterol organization in membranes containing very low amounts of cholesterol has not been investigated extensively. Recent evidence from differential-scanning calorimetric studies suggests that cholesterol may not form uniform monodisperse solutions, as assumed earlier, in the membranes even at very low concentrations. Fluorescent cholesterol analogues, when chosen carefully, offer a powerful approach for studying the distribution and organization of cholesterol in membranes at low concentrations. In this paper, we have studied the organization of cholesterol in membranes at very low concentrations (up to 5 mol % of the total lipid) using a fluorescent cholesterol analogue (NBD-cholesterol) which is labeled with the 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) group at the flexible acyl chain, without any alteration in the structural features necessary for proper membrane incorporation. Our results show that NBD-cholesterol exhibits local organization even at very low concentrations. This is consistent with the recently suggested model of cholesterol organization in membranes at low concentrations, involving the formation of transbilayer, tail-to-tail dimers The fluid mosaic model for biological membranes defines the membrane as an oriented, two-dimensional, viscous solution of proteins and lipids in instantaneous thermodynamic equilibrium (Singer & Nicolson, 1972). Although the basic tenets of this model have stood the test of time, one of its implicit assumptions, that the lipid molecules merely provide the milieu for the membrane proteins and that they are distributed uniformly throughout the bilayer, has been found to be not quite true. In fact, current evidence points out that both transverse and lateral regionalization, which can be described in terms of micro-and macrodomains, are common features of many biological membranes (Curtain et al., 1988;Edidin, 1992;Tocanne, 1992;Glaser, 1993;Jacobson et al., 1995).Cholesterol is one of the membrane components that is found, more often than not, distributed nonrandomly in structural and kinetic domains or pools in both biological and model membranes (Yeagle, 1985;Gennis, 1989;Schroeder et al., 1991;Liscum & Underwood, 1995). The reason for this lies in the rather unusual chemical structure of cholesterol that can by no means be considered a representative component of the "bulk" membrane (see Figure 1). The unusual shape of cholesterol also causes a phase separation in membranes at relatively high concentrations, resulting in the formation of cholesterol-rich and -poor domains that are structurally and compositionally so distinct that they can be observed histochemically and isolated physical...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Membrane Organization at Low Cholesterol Concentrations: A Study Using 7-Nitrobenz-2-oxa-1,3-diazol-4-yl-Labeled Cholesterol

1996

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“…Unesterified cholesterol transfer and exchange occur by a spontaneous process through collision and aqueous diffusion (2,3). In the cell, possible mechanisms of cholesterol movement also include aqueous diffusion, vesicle-mediated transport, and soluble carrier-mediated transport (4). Protein-mediated exchange and transfer of free cholesterol in the plasma have not been fully investigated.…”

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confidence: 99%

Phospholipid Transfer Protein Mediates Transfer of not Only Phosphatidylcholine but Also Cholesterol from Phosphatidylcholine-Cholesterol Vesicles to High Density Lipoproteins

Nishida

1997

Journal of Biological Chemistry

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Phospholipid transfer protein (PLTP) purified from human plasma was found to enhance the transfer of cholesterol from single bilayer vesicles containing phosphatidylcholine and cholesterol to high density lipoprotein-3. The rate of cholesterol transfer was greatly influenced by the cholesterol content of the donor vesicles. The maximal rate was observed with the vesicles containing 20 -25 mol % cholesterol. This was in contrast to a progressive decline in the rate of phosphatidylcholine transfer with an increase in the cholesterol content. To determine the binding of cholesterol and phosphatidylcholine to PLTP, the mixtures of PLTP and the vesicles containing 3 H-labeled phosphatidylcholine and 14 C-labeled cholesterol were incubated and subjected to sucrose density gradient centrifugation. Determination of the label profiles showed that cholesterol as well as phosphatidylcholine were transferred from the vesicles to PLTP. The reversible nature of the binding was shown by the transfer of labeled cholesterol and phosphatidylcholine bound to PLTP to the acceptor vesicles or low density lipoprotein. Isothermal equilibrium binding of PLTP for cholesterol and phosphatidylcholine showed that PLTP possessed a considerably higher affinity and binding capacity for phosphatidylcholine than for cholesterol. The phosphatidylcholine binding affinity and capacity were greater when PLTP was incubated with phosphatidylcholine vesicles without cholesterol. A possible importance of PLTP-mediated cholesterol transfer in the circulation was described.

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“…Substantial cell death, particularly in the cerebellum, accounts for some of the symptoms. At the cellular level, mutant cells accumulate cholesterol and other lipids in aberrant compartments with features of late endosomes and lysosomes, and the normal homeostatic response to this excess cholesterol is abolished (2)(3)(4).…”

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confidence: 99%

The integrity of a cholesterol-binding pocket in Niemann–Pick C2 protein is necessary to control lysosome cholesterol levels

Binkley

Sidow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

182

196

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The neurodegenerative disease Niemann-Pick Type C2 (NPC2) results from mutations in the NPC2 (HE1) gene that cause abnormally high cholesterol accumulation in cells. We find that purified NPC2, a secreted soluble protein, binds cholesterol specifically with a much higher affinity (K d ‫؍‬ 30 -50 nM) than previously reported. Genetic and biochemical studies identified single amino acid changes that prevent both cholesterol binding and the restoration of normal cholesterol levels in mutant cells. The amino acids that affect cholesterol binding surround a hydrophobic pocket in the NPC2 protein structure, identifying a candidate sterol-binding location. On the basis of evolutionary analysis and mutagenesis, three other regions of the NPC2 protein emerged as important, including one required for efficient secretion.point mutants ͉ secretion ͉ protein evolution N iemann-Pick Type C (NPC) is an autosomal-recessive disorder characterized by progressive ataxia, dystonia, and dementia (1). Substantial cell death, particularly in the cerebellum, accounts for some of the symptoms. At the cellular level, mutant cells accumulate cholesterol and other lipids in aberrant compartments with features of late endosomes and lysosomes, and the normal homeostatic response to this excess cholesterol is abolished (2-4).Our understanding of the molecular basis of this disease has progressed substantially over the last several years, because the two genes damaged by NPC mutations, NPC1 and NPC2, have been identified (5-7). NPC1 encodes a multiple-membranespanning protein containing sequences similar to the sterol cleavage activating protein (SCAP) regulator of cholesterol metabolism and the receptor Patched, a transducer of the Hedgehog family of protein signals. Mutations in NPC1 are responsible for Ϸ95% of the NPC cases (8). The exact role that NPC1 plays in maintaining normal levels of cholesterol in late endosomes and lysosomes remains mysterious. Even less is known about the NPC2 [human epididymis (HE1)] protein, the loss of which is responsible for 5% of NPC cases.NPC2 is a small secreted glycoprotein originally identified as a transcript enriched in the HE1 (9). The porcine HE1 homolog was reported to bind cholesterol with micromolar affinity (K d ϭ 2.3 M; ref. 10), information that was crucial in identifying HE1 as a candidate npc2 gene product (7). However, the similarity between the reported K d and the solubility of cholesterol in aqueous solution (5 M, Merck Index) warrants reexamination of the strength and specificity of this interaction. If the binding is meaningful, NPC2 activity could be altered when cholesterol is bound, thus serving as a sensor of cholesterol levels, accessibility, or location. Alternatively, NPC2 could process or transport cholesterol. Resolving these questions is crucial for determining why cholesterol accumulates in people lacking functional NPC2 protein and for designing rational treatment strategies.In this report, we combine in vitro binding experiments, genetic analysis, a quantitative cell-based ...

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Intracellular Cholesterol Transport and Compartmentation

Cited by 252 publications

References 60 publications

Membrane Organization at Low Cholesterol Concentrations: A Study Using 7-Nitrobenz-2-oxa-1,3-diazol-4-yl-Labeled Cholesterol

Membrane Organization at Low Cholesterol Concentrations: A Study Using 7-Nitrobenz-2-oxa-1,3-diazol-4-yl-Labeled Cholesterol

Phospholipid Transfer Protein Mediates Transfer of not Only Phosphatidylcholine but Also Cholesterol from Phosphatidylcholine-Cholesterol Vesicles to High Density Lipoproteins

The integrity of a cholesterol-binding pocket in Niemann–Pick C2 protein is necessary to control lysosome cholesterol levels

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