Top 10 HDL papers for 2006

Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice. Lai Wang, Behrooz G. Sharifi, Theresa Pan, Lei Song, Ada Yukht, and Prediman K. Shah. Journal of the American College of Cardiology 2006; 48:1459-68.

This study uses gene therapy to directly compare how expression of wild-type apolipoprotein A-I (apoA-I) and a variant, apoA-IMilano, in macrophages affects atherosclerotic lesion development in the mouse. The results show that the ability of apoA-IMilano to reduce atherosclerosis is superior to that of wild type apoA-I. This difference was apparent at comparable levels of expression of the two forms of apoA-I, and in the absence of significant changes in lipoprotein profiles. These results are attributed, at least in part, to the enhanced ability of apoA-IMilano to efflux cholesterol from macrophages. It remains to be seen if this is also the case for humans.

HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway
Fumihiko Matsuura, Nan Wang, Wengen Chen, Xian-Cheng Jiang, and Alan R. Tall The Journal of Clinical Investigation 2006;116:1435-42.

This report shows for the first time that the large HDL from homozygous, cholesteryl ester transfer protein (CETP)-deficient subjects are 2-3 fold more effective at accepting cholesterol from macrophages than HDL from normal individuals. Evidence that this effect is dependent on the presence of the ATP-binding cassette transporter, ABCG1, in the cell membrane is also presented.

Role of scavenger receptor class B type I and sphingosine-1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells
Takao Kimura, Hideaki Tomura, Chihiro Mogi, et al. The Journal of Biological Chemistry 2006;281:37457–67.

This study investigates the mechanism whereby HDL inhibit cytokine-induced adhesion molecule expression in endothelial cells, thereby attenuating the events that initiate the inflammatory response. The results are consistent with HDL inhibiting the activation of NF-κB, a key inflammatory mediator, by two pathways. One pathway involves the interaction of HDL with the scavenger receptor B1 (which is better known as the receptor responsible for the selective uptake of cholesteryl esters from HDL). This interaction activates endothelial nitric oxide synthase (eNOS) and the formation of NO, which inhibits NF-κB activation directly. The other pathway involves the interaction of sphingosine-1-phosphate, one of the surface constituents of HDL, with a specific sphingosine-1-phosphate receptor on the cell surface, which then activates eNOS and inhibits NF-κB activation.

High-density lipoproteins and their constituent sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor
Gregor Theilmeier, Christoph Schmidt, Jörg Herrmann, et al. Circulation 2006;114:1403-9.

HDL have previously been shown to protect against ischaemia/reperfusion injury in isolated rat hearts by reducing the level of the cytokine, tumour necrosis factor-alpha, and increasing prostaglandins (Circ Res 2003;92:330-7). This new study shows that sphingosine-1-phosphate and HDL can also decrease infarction size by suppressing the recruitment of neutrophils into the artery wall and inhibiting cardiomyocyte apoptosis. These beneficial effects were related to nitric oxide formation and the interaction of sphingosine-1-phosphate with the sphingosine-1-phosphate receptor. The results suggest that the ability of HDL to prevent ischaemia/reperfusion injury may be directly related to their sphingosine-1-phosphate content.

Adipose tissue-specific CETP expression in mice: impact on plasma lipoprotein metabolism
Hongwen Zhou, Zhiqiang Li, Mohamad R. Hojjati, et al. Journal of Lipid Research 2006; 47:2011–19.

This study investigated how CETP in adipose tissue impacts on lipoprotein metabolism using a mouse model. As mice are naturally deficient in CETP, the investigators genetically engineered mice to express CETP in adipocytes. Substantial levels of CETP mass and activity were present in the plasma of the transgenic animals. This was associated with significantly reduced HDL and increased low-density lipoprotein (LDL) levels. Expression of CETP also decreased the size, as well as the cholesterol and triglyceride content, of the adipocytes. These results indicate that adipocyte CETP makes a major contribution to lipoprotein metabolism.

Mechanism of prebeta-HDL formation and activation
Phuonglan Chau, Yasushi Nakamura, Christopher J. Fielding, and Phoebe E. Fielding Biochemistry 2006;45:3981-7.

Prebeta HDL consist of a single molecule of apoA-I complexed with a small amount of lipid. These particles are the main acceptors of the cholesterol that is exported from cells (including macrophages in the artery wall) in the first step of the potentially anti- atherogenic reverse cholesterol transport pathway. This study elucidates the mechanism of formation of prebeta HDL by showing that the lipid-free apoA-I which is secreted from cells is unable to interact with either phospholipids or unesterified cholesterol until it undergoes an ABCA1-dependent reorganization. This reorganization converts the secreted apoA-I from a prealpha-migrating form to a prebeta-migrating form that can accept phospholipids. The resulting prebeta-migrating phospholipid/apoA-I complex is then able to participate in the first step of reverse cholesterol transport by accepting cellular cholesterol.

Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo
Roshni R. Singaraja, Miranda Van Eck, Nagat Bissada, et al. Circulation 2006;114:1301-9.

This study investigates the relative contributions of hepatic and extrahepatic ABCA1 to HDL levels in the mouse. The results show that when ABCA1 is expressed only in the liver, plasma HDL levels cannot be maintained. Expression of ABCA1 in extrahepatic tissues is shown to be essential for generating mature HDL. The authors conclude that hepatic ABCA1 exports phospholipids to lipid-free or lipid-poor apoA-I to generate prebeta HDL, while the ABCA1 in extrahepatic tissues is involved in the maturation of prebeta HDL by a process that involves the export of cholesterol to the particles.

Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I protein synthesis and enhancing HDL cholesterol clearance.
Dan Liao, Hongmei Tan, Rutai Hui, et al. Circulation Research 2006;99:598-606.

This study investigates the mechanism responsible for the reduced HDL cholesterol levels that accompany hyperhomocysteinemia. This was achieved using apolipoprotein E-deficient mice that were also genetically manipulated to have high homocysteine levels. The results show that the low HDL levels in these mice are caused by a reduction in apoA-I synthesis as well as increased clearance of HDL cholesteryl esters. The investigators also indicate that the inability of the apoA-I in the hyperhomocysteinemic animals to activate lecithin:cholesterol acyltransferase (LCAT) as well as the apoA-I in wild-type mice may contribute to the reduced HDL levels, and that increased expression of SR-B1 is responsible for the increased clearance of HDL cholesteryl esters.

High-density lipoprotein hydrolysis by endothelial lipase activates PPARα: a candidate mechanism for high-density lipoprotein–mediated repression of leukocyte adhesion
Waleed Ahmed, Gabriela Orasanu, Vedika Nehra, et al. Circulation Research 2006;98:490-8.

This study documents another mechanism whereby HDL inhibit adhesion molecule expression in cytokine-activated endothelial cells. Endothelial lipase is a member of the triglyceride lipase family that preferentially hydrolyses HDL phospholipids. The results show that the hydrolysis of HDL phospholipids by endothelial lipase activates peroxisome proliferator-activated receptor α (PPARα), and this in turn inhibits adhesion molecule expression. The authors indicate that PPARα activation is most likely caused by the release of fatty acids from HDL as a consequence of endothelial lipase-mediated phospholipid hydrolysis.

High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I
Divya Seetharam, Chieko Mineo, Andrew K. Gormley, et al. Circulation Research 2006; 98:63-72.

This study shows that HDL protect against atherosclerosis by promoting endothelial repair both in cultured aortic endothelial cells and in an animal model of carotid artery injury. The mechanism of endothelial repair involves an initial interaction of HDL with SR-B1 followed by the activation of intracellular signalling pathways, and cytoskeletal lamellipodia formation. This leads to enhanced endothelial cell migration and increases endothelial integrity.