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Caveolin, cholesterol, and lipid droplets?

van Meer G - J. Cell Biol. (2001)

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, Netherlands. g.vanmeer@amc.uva.nl

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Caveolins constitute the coat of caveolae, specialized domains of the plasma membrane... Caveolin-2 is mostly coexpressed with caveolin-1, and the two can form heterooligomers... The structure of caveolae depends on cholesterol, and caveolins were found to be cholesterol-binding proteins that end up in detergent-resistant membrane remnants, which are generally interpreted as originating from sphingolipid–cholesterol rafts... Typical raft markers like glycosylphosphatidylinositol proteins and glycosphingolipids were found in caveolae under specific conditions... At the same time, the exciting finding of cytosolic signaling molecules in caveolae has led to a wide interest in caveolae as being cell surface domains where signaling is partially regulated via the physical state of the lipids... Various interpretations of the data are possible. (a) Some droplets are still physically connected to the ER membrane (Blanchette-Mackie et al. 1995), giving the impression that the ER bilayer covers the droplet. (b) In some EM studies, the core lipids are extracted during the embedding procedure (McGookey and Anderson 1983), and the surface monolayer may have reoriented into a fragmented bilayer. (c) A lipid bilayer cannot cover the triacylglycerol-cholesterol ester core directly... Lipid particles covered by a lipid monolayer could bud into the ER lumen, but that is not where they are found... Probably, the remnants are removed by phospholipases and proteolytic enzymes... A breakthrough in our understanding of caveolins and cholesterol may come from the present reports that caveolins are found on lipid droplets (Fujimoto et al. 2001; Ostermeyer et al. 2001; Pol et al. 2001)... First of all, the retention of caveolin-1 by the added retrieval signal indicates that caveolin-1 is inserted into the ER membrane and is normally transported to the plasma membrane by the exocytic pathway (Ostermeyer et al. 2001)... In addition, this demonstrates that lipid droplets are not an intermediary station for caveolins in a rapid transport pathway from the ER to Golgi and plasma membrane... (a) Caveolins could have affinity for the droplet cholesterol that is present in the core in the form of cholesterol ester... Although an interesting possibility, reduction of cholesterol esters by 80% did not reduce droplet caveolin (Ostermeyer et al. 2001)... The latter possibility is supported by the observations that, upon dissolution of the lipid droplet by Triton X-100, the caveolins stuck to some fibrous protein right next to the droplet, and that truncated caveolin-3 seemed to move as a wave into a newly forming droplet (Pol et al. 2001). (c) Caveolins and ADRP could be expelled from the ER onto the free droplet surface by transmembrane proteins. (d) Finally, fusion of new lipid droplets to preexisting ones in the cytosol would generate excess membrane relative to volume.

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Model for cholesterol recycling through the endocytic pathway. In the lumenal leaflet of the trans-Golgi network (A), sphingolipids and cholesterol (blue) segregate from phospholipids. In epithelial cells, the sphingolipid–cholesterol rafts are transported to the apical surface, the phospholipids to the basolateral surface. In nonpolarized cells both pathways target the plasma membrane (B). From the plasma membrane the sphingolipids are endocytosed (from caveolae?) as are the phospholipids (from clathrin-coated buds?), into common early endosomes (C). There the phospholipids are sorted into a recycling pathway, whereas the sphingolipids travel to the late endosomes (D), which have obtained internal vesicles by budding from the limiting membrane. From here, the sphingolipids and cholesterol recycle to the Golgi and the plasma membrane. This budding step may be regulated by caveolin.
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Figure 1: Model for cholesterol recycling through the endocytic pathway. In the lumenal leaflet of the trans-Golgi network (A), sphingolipids and cholesterol (blue) segregate from phospholipids. In epithelial cells, the sphingolipid–cholesterol rafts are transported to the apical surface, the phospholipids to the basolateral surface. In nonpolarized cells both pathways target the plasma membrane (B). From the plasma membrane the sphingolipids are endocytosed (from caveolae?) as are the phospholipids (from clathrin-coated buds?), into common early endosomes (C). There the phospholipids are sorted into a recycling pathway, whereas the sphingolipids travel to the late endosomes (D), which have obtained internal vesicles by budding from the limiting membrane. From here, the sphingolipids and cholesterol recycle to the Golgi and the plasma membrane. This budding step may be regulated by caveolin.

Mentions: Cholesterol accumulates in late endosomes in a variety of diseases and experimental conditions (Liscum and Munn 1999). In all cases, there appears to be an accumulation of lipids that can trap cholesterol (like sphingomyelin, half-time of cholesterol desorption is ∼15 h; Phillips et al. 1987), and a defect in vesicle budding from and into late endosomes. The exact order of events is presently unclear, but two proteins involved in cholesterol transport, the Niemann-Pick type C disease protein (Davies et al. 2000) and the Tangier disease ABCA1 protein (Hamon et al. 2000), may be lipid translocators. Proper hydrolysis and removal of lipids, especially sphingolipids like sphingosine, from endosomes may be required for allowing vesicular transport of cholesterol from the endosomes to Golgi and plasma membrane (Fig. 1).


Caveolin, cholesterol, and lipid droplets?

van Meer G - J. Cell Biol. (2001)

Model for cholesterol recycling through the endocytic pathway. In the lumenal leaflet of the trans-Golgi network (A), sphingolipids and cholesterol (blue) segregate from phospholipids. In epithelial cells, the sphingolipid–cholesterol rafts are transported to the apical surface, the phospholipids to the basolateral surface. In nonpolarized cells both pathways target the plasma membrane (B). From the plasma membrane the sphingolipids are endocytosed (from caveolae?) as are the phospholipids (from clathrin-coated buds?), into common early endosomes (C). There the phospholipids are sorted into a recycling pathway, whereas the sphingolipids travel to the late endosomes (D), which have obtained internal vesicles by budding from the limiting membrane. From here, the sphingolipids and cholesterol recycle to the Golgi and the plasma membrane. This budding step may be regulated by caveolin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198809&req=5

Figure 1: Model for cholesterol recycling through the endocytic pathway. In the lumenal leaflet of the trans-Golgi network (A), sphingolipids and cholesterol (blue) segregate from phospholipids. In epithelial cells, the sphingolipid–cholesterol rafts are transported to the apical surface, the phospholipids to the basolateral surface. In nonpolarized cells both pathways target the plasma membrane (B). From the plasma membrane the sphingolipids are endocytosed (from caveolae?) as are the phospholipids (from clathrin-coated buds?), into common early endosomes (C). There the phospholipids are sorted into a recycling pathway, whereas the sphingolipids travel to the late endosomes (D), which have obtained internal vesicles by budding from the limiting membrane. From here, the sphingolipids and cholesterol recycle to the Golgi and the plasma membrane. This budding step may be regulated by caveolin.
Mentions: Cholesterol accumulates in late endosomes in a variety of diseases and experimental conditions (Liscum and Munn 1999). In all cases, there appears to be an accumulation of lipids that can trap cholesterol (like sphingomyelin, half-time of cholesterol desorption is ∼15 h; Phillips et al. 1987), and a defect in vesicle budding from and into late endosomes. The exact order of events is presently unclear, but two proteins involved in cholesterol transport, the Niemann-Pick type C disease protein (Davies et al. 2000) and the Tangier disease ABCA1 protein (Hamon et al. 2000), may be lipid translocators. Proper hydrolysis and removal of lipids, especially sphingolipids like sphingosine, from endosomes may be required for allowing vesicular transport of cholesterol from the endosomes to Golgi and plasma membrane (Fig. 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, Netherlands. g.vanmeer@amc.uva.nl

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Caveolins constitute the coat of caveolae, specialized domains of the plasma membrane... Caveolin-2 is mostly coexpressed with caveolin-1, and the two can form heterooligomers... The structure of caveolae depends on cholesterol, and caveolins were found to be cholesterol-binding proteins that end up in detergent-resistant membrane remnants, which are generally interpreted as originating from sphingolipid–cholesterol rafts... Typical raft markers like glycosylphosphatidylinositol proteins and glycosphingolipids were found in caveolae under specific conditions... At the same time, the exciting finding of cytosolic signaling molecules in caveolae has led to a wide interest in caveolae as being cell surface domains where signaling is partially regulated via the physical state of the lipids... Various interpretations of the data are possible. (a) Some droplets are still physically connected to the ER membrane (Blanchette-Mackie et al. 1995), giving the impression that the ER bilayer covers the droplet. (b) In some EM studies, the core lipids are extracted during the embedding procedure (McGookey and Anderson 1983), and the surface monolayer may have reoriented into a fragmented bilayer. (c) A lipid bilayer cannot cover the triacylglycerol-cholesterol ester core directly... Lipid particles covered by a lipid monolayer could bud into the ER lumen, but that is not where they are found... Probably, the remnants are removed by phospholipases and proteolytic enzymes... A breakthrough in our understanding of caveolins and cholesterol may come from the present reports that caveolins are found on lipid droplets (Fujimoto et al. 2001; Ostermeyer et al. 2001; Pol et al. 2001)... First of all, the retention of caveolin-1 by the added retrieval signal indicates that caveolin-1 is inserted into the ER membrane and is normally transported to the plasma membrane by the exocytic pathway (Ostermeyer et al. 2001)... In addition, this demonstrates that lipid droplets are not an intermediary station for caveolins in a rapid transport pathway from the ER to Golgi and plasma membrane... (a) Caveolins could have affinity for the droplet cholesterol that is present in the core in the form of cholesterol ester... Although an interesting possibility, reduction of cholesterol esters by 80% did not reduce droplet caveolin (Ostermeyer et al. 2001)... The latter possibility is supported by the observations that, upon dissolution of the lipid droplet by Triton X-100, the caveolins stuck to some fibrous protein right next to the droplet, and that truncated caveolin-3 seemed to move as a wave into a newly forming droplet (Pol et al. 2001). (c) Caveolins and ADRP could be expelled from the ER onto the free droplet surface by transmembrane proteins. (d) Finally, fusion of new lipid droplets to preexisting ones in the cytosol would generate excess membrane relative to volume.

Show MeSH
Related in: MedlinePlus