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News on the cradle of atherosclerosis
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News & Comment
TRENDS in Cell Biology Vol.12 No.9 September 2002
News on the cradle of atherosclerosis The processes initiating atherosclerosis that eventually lead to all the well-known complications of the disease have long been debated. Now, Borén and coworkers provide convincing data on the first steps of atherogenesis [1]. Their findings indicate that the central event in the development of atherosclerosis is the retention of lowdensity lipoprotein (LDL) by proteoglycans present in the subendothelium. In particular, stretches of basic amino acids in LDL bind to the negatively charged sulfate groups of the proteoglycans. The results showing the importance of LDL–proteoglycan interactions are based on
studies with transgenic mice expressing various forms of human recombinant LDL (containing specific mutations in apolipoprotein B) that are defective in either proteoglycan or LDL receptor binding. Thus, there was a clear correlation between the ability of LDL to bind to proteoglycans and LDL retention in the artery wall. The study was performed with a variety of controls to exclude other reasons for the observed differences. Notably, increased amounts of apolipoprotein E (apoE) that also favour interaction of LDL with proteoglycans could restore the reduced binding of proteoglycanbinding-defective LDL in mice. As apoE is not
found on human LDL, this might not be relevant for atherogenesis in humans. It will now be interesting to see whether measures can be developed that interfere pharmacologically with the strong interaction between LDL and proteoglycans in a regulatable manner, thus perhaps paving the way to new therapeutic strategies for atherosclerosis and coronary heart disease. 1 Skålén, K. et al. (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754
N. Erwin Ivessa [email protected]
Collagen and tissue morphogenesis Collagen is the most abundant protein in the vertebrate body, contributing a scaffold to the skeleton and most connective tissues. A major unresolved question in cell biology concerns the mechanism for organizing the collagen fibers during tissue morphogenesis. Collagen reorganization is also important in a number of disease processes, including the formation of the atherosclerotic plaque in arterial occlusive disease. A recent elegant paper hypothesizes a mechanism for cellular reorganization of collagen matrices [1]. In recent years, it has become clear that collagen-binding integrins serve as the contact point between cells and collagen fibrils. However, little is known about the
mechanism whereby cell pulling on collagen fibers organizes the fibers into distinct tissue structures. Almost two decades ago, data emerged indicating that fibroblast traction (drawing) forces serve to organize collagen matrices and work as the driving force for collagen patterning. Little progress has been made since then in understanding how the traction seen in vitro operates in vivo during tissue morphogenesis. Sawhney and Howard embedded cells in collagen gels and then tracked the movement of glass beads in the gel to calculate anisotropy with the aid of a new computer algorithm [1]. Surprisingly, small movements around cells rapidly spread into
the gel. The authors suggest that the rapid spreading and amplification of the collagen rearrangement is due to the specific organization of the collagen meshwork (which they illustrate in a geometric model). The simple experimental set-up, combined with the sophisticated data handling, results in a fascinating model that might also hold true for intracellular protein meshworks. 1 Sawhney, R.K. and Howard, J. (2002) Slow local movements of collagen fibers by fibroblasts drive the rapid global self-organization of collagen gels. J. Cell Biol. 157, 1083–1091
Donald Gullberg [email protected]
The SREBP pathway: PtdEtn joins cholesterol to expand the paradigm A feedback mechanism that plays out in the endomembrane system is taking shape as a major regulator of the lipid composition of cellular membranes. Studied intensively in the context of cholesterol homeostasis, the mechanism was found to be based on a transcription factor called SREBP (sterol response element binding protein) that remains tethered to the endoplasmic reticulum (ER) membrane in cholesterolreplete cells. When cholesterol levels fall, SREBP departs the ER for the Golgi, where a pair of proteases release its transcriptionactivating domain from the cytoplasmic side of the membrane. Free to enter the nucleus, SREBP turns on genes encoding http://tcb.trends.com
cholesterol-biosynthetic enzymes. A second protein called SCAP (SREBP cleavageactivating protein) is the sensor that detects low cholesterol levels and escorts SREBP from the ER to the Golgi. Recent reports from the Brown and Goldstein group suggest that the SREBP pathway is a general monitor of membrane lipids, with the cholesterol-regulated mechanism just one specifically evolved permutation. A key insight came from the observation that, despite the absence of sterols in insects, the Drosophila genome encodes a complete set of machinery for the SREBP pathway [1]. Not surprisingly then, regulators of SREBP in mammalian cells are without effect in insect
cells. Rather, the saturated fatty acid palmitate causes SREBP to be retained in the ER [1]. In a technical tour-de-force, the group now reports that palmitate probably exerts its effect through its input into phosphatidylethanolamine (PtdEtn) synthesis[2]. Systematic use of RNAi and other reagents to perturb steps in sphingolipid metabolism showed that palmitate blocks SREBP cleavage through its role as a metabolic source of phosphoethanolamine, the donor of ethanolamine head groups in PtdEtn synthesis. By retaining SREBP in the ER, PtdEtn blocks accumulation of mRNAs for enzymes in fatty acid and phospholipid synthesis[2]. Thus feedback inhibition
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
News & Comment
TRENDS in Cell Biology Vol.12 No.9 September 2002
News on the cradle of atherosclerosis The processes initiating atherosclerosis that eventually lead to all the well-known complications of the disease have long been debated. Now, Borén and coworkers provide convincing data on the first steps of atherogenesis [1]. Their findings indicate that the central event in the development of atherosclerosis is the retention of lowdensity lipoprotein (LDL) by proteoglycans present in the subendothelium. In particular, stretches of basic amino acids in LDL bind to the negatively charged sulfate groups of the proteoglycans. The results showing the importance of LDL–proteoglycan interactions are based on
studies with transgenic mice expressing various forms of human recombinant LDL (containing specific mutations in apolipoprotein B) that are defective in either proteoglycan or LDL receptor binding. Thus, there was a clear correlation between the ability of LDL to bind to proteoglycans and LDL retention in the artery wall. The study was performed with a variety of controls to exclude other reasons for the observed differences. Notably, increased amounts of apolipoprotein E (apoE) that also favour interaction of LDL with proteoglycans could restore the reduced binding of proteoglycanbinding-defective LDL in mice. As apoE is not
found on human LDL, this might not be relevant for atherogenesis in humans. It will now be interesting to see whether measures can be developed that interfere pharmacologically with the strong interaction between LDL and proteoglycans in a regulatable manner, thus perhaps paving the way to new therapeutic strategies for atherosclerosis and coronary heart disease. 1 Skålén, K. et al. (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754
N. Erwin Ivessa [email protected]
Collagen and tissue morphogenesis Collagen is the most abundant protein in the vertebrate body, contributing a scaffold to the skeleton and most connective tissues. A major unresolved question in cell biology concerns the mechanism for organizing the collagen fibers during tissue morphogenesis. Collagen reorganization is also important in a number of disease processes, including the formation of the atherosclerotic plaque in arterial occlusive disease. A recent elegant paper hypothesizes a mechanism for cellular reorganization of collagen matrices [1]. In recent years, it has become clear that collagen-binding integrins serve as the contact point between cells and collagen fibrils. However, little is known about the
mechanism whereby cell pulling on collagen fibers organizes the fibers into distinct tissue structures. Almost two decades ago, data emerged indicating that fibroblast traction (drawing) forces serve to organize collagen matrices and work as the driving force for collagen patterning. Little progress has been made since then in understanding how the traction seen in vitro operates in vivo during tissue morphogenesis. Sawhney and Howard embedded cells in collagen gels and then tracked the movement of glass beads in the gel to calculate anisotropy with the aid of a new computer algorithm [1]. Surprisingly, small movements around cells rapidly spread into
the gel. The authors suggest that the rapid spreading and amplification of the collagen rearrangement is due to the specific organization of the collagen meshwork (which they illustrate in a geometric model). The simple experimental set-up, combined with the sophisticated data handling, results in a fascinating model that might also hold true for intracellular protein meshworks. 1 Sawhney, R.K. and Howard, J. (2002) Slow local movements of collagen fibers by fibroblasts drive the rapid global self-organization of collagen gels. J. Cell Biol. 157, 1083–1091
Donald Gullberg [email protected]
The SREBP pathway: PtdEtn joins cholesterol to expand the paradigm A feedback mechanism that plays out in the endomembrane system is taking shape as a major regulator of the lipid composition of cellular membranes. Studied intensively in the context of cholesterol homeostasis, the mechanism was found to be based on a transcription factor called SREBP (sterol response element binding protein) that remains tethered to the endoplasmic reticulum (ER) membrane in cholesterolreplete cells. When cholesterol levels fall, SREBP departs the ER for the Golgi, where a pair of proteases release its transcriptionactivating domain from the cytoplasmic side of the membrane. Free to enter the nucleus, SREBP turns on genes encoding http://tcb.trends.com
cholesterol-biosynthetic enzymes. A second protein called SCAP (SREBP cleavageactivating protein) is the sensor that detects low cholesterol levels and escorts SREBP from the ER to the Golgi. Recent reports from the Brown and Goldstein group suggest that the SREBP pathway is a general monitor of membrane lipids, with the cholesterol-regulated mechanism just one specifically evolved permutation. A key insight came from the observation that, despite the absence of sterols in insects, the Drosophila genome encodes a complete set of machinery for the SREBP pathway [1]. Not surprisingly then, regulators of SREBP in mammalian cells are without effect in insect
cells. Rather, the saturated fatty acid palmitate causes SREBP to be retained in the ER [1]. In a technical tour-de-force, the group now reports that palmitate probably exerts its effect through its input into phosphatidylethanolamine (PtdEtn) synthesis[2]. Systematic use of RNAi and other reagents to perturb steps in sphingolipid metabolism showed that palmitate blocks SREBP cleavage through its role as a metabolic source of phosphoethanolamine, the donor of ethanolamine head groups in PtdEtn synthesis. By retaining SREBP in the ER, PtdEtn blocks accumulation of mRNAs for enzymes in fatty acid and phospholipid synthesis[2]. Thus feedback inhibition
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.